WO2025076109A1 - Utilisation d'élesclomol pour le traitement des cancers ovariens à cellules claires avec des mutations de l'arid1a - Google Patents

Utilisation d'élesclomol pour le traitement des cancers ovariens à cellules claires avec des mutations de l'arid1a Download PDF

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WO2025076109A1
WO2025076109A1 PCT/US2024/049622 US2024049622W WO2025076109A1 WO 2025076109 A1 WO2025076109 A1 WO 2025076109A1 US 2024049622 W US2024049622 W US 2024049622W WO 2025076109 A1 WO2025076109 A1 WO 2025076109A1
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elesclomol
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optionally substituted
derivative
analog
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WO2025076109A9 (fr
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Dennis Brown
Jeffrey BACHA
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Edison Oncology Holding Corp
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Edison Oncology Holding Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention is directed to compositions and methods employing elesclomol or derivatives or analogs thereof or related redox agents for treatment of malignancies, particularly ovarian clear-cell carcinoma in patients with mutations in ARID1A.
  • BACKGROUND OF THE INVENTION [0003] The search for and identification of cures for many life-threatening diseases that plague humans still remains an empirical and sometimes serendipitous process. While many advances have been made from basic scientific research to improvements in practical patient management, there still remains tremendous frustration in the rational and successful discovery and application of useful therapies, particularly for life-threatening diseases such as cancer, immune-mediated diseases, inflammatory conditions, and infections, as well as other diseases and conditions such as neurodegenerative conditions.
  • Cells with mutations in ARID1A may also have mutations in PTEN, a phosphatase that in its wild-type form acts as a tumor suppressor.
  • OCCC cells rarely carry mutations in TP53, BRCA1, or BRCA2. In addition, they also test negative for estrogen and progesterone receptors and Wilm tumor suppressor 1. Studies have also suggested that clear-cell carcinoma can occur with thromboembolic complications and PATENT EDISON-58717 hypercalcemia. Recurrence of tumor cells have been reported to involve lymph nodes and parenchymal organs. A suggested mechanism associated with OCCC tumor progression is the amplification of the CCNE gene leading to overexpression of cyclin E1 protein. [0009] Detecting the cancerous tumor progression can be difficult for pathologists.
  • OCCC can frequently be cured by surgical removal of the ovary or a portion of the ovary. However, if the tumor is only diagnosed beyond FIGO stage 1, patients usually have a poor prognosis. OCCC can be fatal if the tumors metastasize and spread throughout the body. Additionally, OCCC is typically resistant to conventional chemotherapy used to treat ovarian carcinoma such as platinum-containing agents or taxanes.
  • One aspect of the invention is a method to improve the efficacy and/or reduce the side effects of the administration of elesclomol or a derivative, analog, salt, or solvate of elesclomol for treatment of ovarian clear-cell carcinoma (OCCC) comprising the steps of: (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the administration of the elesclomol or a derivative, analog, salt, or solvate of elesclomol for the treatment of OCCC; and (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the administration of the elesclomol or a derivative, analog, salt, or solvate of PATENT EDISON-58717 elesclomol for the treatment of OCCC.
  • OCCC ovarian clear-cell carcinoma
  • the therapeutically effective quantity of elesclomol is from about 1 ⁇ g/kg to about 500 mg/kg, typically from about 500 ⁇ g/kg to about 250 mg/kg, preferably from about 1 mg/kg to about 100 mg/kg, more preferably from about 10 mg/kg to about 50 mg/kg.
  • the therapeutically effective quantity of elesclomol or the derivative, analog, salt, or solvate of elesclomol is administered in a pharmaceutical composition.
  • Another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of a PARP inhibitor.
  • Yet another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of a glutamine metabolism inhibitor.
  • Still another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of an agent that causes tumor cells to rely on oxidative phosphorylation.
  • Yet another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of an agent that is an inhibitor of the base excision repair (BER) pathway.
  • BER base excision repair
  • Yet another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of an agent that activates the homologous repair pathway.
  • Still another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of an agent that is activated by bioreductases under acute conditions of hypoxia or that functions to sensitize hypoxic cells to antineoplastic agents or radiation.
  • Yet another aspect of the invention is a method for treatment of OCCC by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol comprising: (1) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (2) administering a therapeutically effective quantity of an agent that inhibits cysteine uptake.
  • the elesclomol or the derivative, analog, salt, or solvate of elesclomol is elesclomol.
  • the elesclomol is in the form of a coordinate- covalent complex with a transition metal cation selected from the group consisting of Ni 2+ , Cu + , Cu 2+ , Co 2+ , Co 3+ , Fe 2+ , Fe 3+ , Zn 2+ , Pt 2+ , Pd 2+ , V 4+ , V 5+ , Cr 2+ , Cr 3+ , Cr 4+ , Mn 2+ , Mn 3+ , Mn 4+ , and Mn 5+ .
  • the additional therapeutic agent can be selected from the group consisting of a microtubulin stabilizer, a microtubulin inhibitor, a PARP inhibitor, an LDH inhibitor, 2-deoxyglucose or an analog or derivative thereof, a glutamine metabolism inhibitor, a DNA-damaging agent, an agent that inhibits the SWI/SNF complex, an agent that causes tumor cells to rely on oxidative phosphorylation, an agent that is an inhibitor of the base excision repair (BER) pathway, an agent that acts as an inhibitor of the homologous repair pathway, an agent that acts as an activator of the homologous repair pathway, an agent that is activated by bioreductases under acute conditions of hypoxia or that functions to sensitize hypoxic cells to antineoplastic agents or radiation, and an agent that inhibits cysteine uptake.
  • BER base excision repair
  • Figure 2 is a diagram showing the involvement of ARID1A in pathways of tumor growth, tumor migration, tumor invasion, and angiogenesis.
  • Figure 3 is a graph showing that progression free survival in patients exhibiting an ARID1A-deficient phenotype is significantly reduced as compared with ARID1A wild-type in patients treated with PARP inhibitors: (A) showing the impact of ARID1A loss, determined via mutation, homozygous deletion, or loss of expression, and survival in TCGA serous ovarian cancers; (B) showing the progression-free survival of relapsed, platinum-sensitive, high-grade ovarian carcinomas in a clinical trial of rucaparib (a PARP inhibitor), stratified based on ARID1A mutation status.
  • A showing the impact of ARID1A loss, determined via mutation, homozygous deletion, or loss of expression, and survival in TCGA serous ovarian cancers
  • B showing the progression-free survival of relapsed, platinum-sensitive, high-grade ovarian carcinomas in a clinical trial of
  • Figure 4 is a graph showing that loss of ARID1A expression correlates with shorter progression-free survival in ovarian clear cell carcinoma patients who received primary cytoreductive surgery followed by standard platinum-based chemotherapy:
  • Figure 5 is a graph showing that loss of ARID1A results in downregulation of cystine transporter SLC7A11 and impairment of GSH pathway leading to ROS accumulation and cell death:
  • A ARID1A complex associated with NRF2 in high ROS environment promotes transcription of SLC7A11 and increased cystine uptake and activation of GHS antioxidant pathway.
  • B Loss of ARID1A inhibits cystine uptake resulting in reduced antioxidant capacity within the cell and increased susceptibility to ROS-driven cell death.
  • Figure 6 is a graph that shows the difference between cells with ARID1A mutations and cells with active ARID1A in terms of the effect of accumulation of ROS:
  • A ARID1A complex associated with NRF2 in high ROS environment promotes transcription of SLC7A11 and increased cystine uptake and activation of GHS antioxidant pathway.
  • B Loss of ARID1A inhibits cystine uptake resulting in reduced antioxidant capacity within the cell and increased susceptibility to ROS-driven cell death.
  • PATENT EDISON-58717 [0046]
  • Figure 7 is a graph that shows a therapeutic window for cancer cells in the presence of an OXPHOS inhibitor.
  • Top Panel Normal body cells have moderate ATP demand and adequate levels of oxygen and glucose and survive in presence of OXPHOS inhibitors by upregulating glycolysis to meet their ATP demands.
  • Middle Panel Highly proliferating cancer cells have extraordinarily high ATP demand and adequate levels of oxygen and glucose. Despite glycolytic pathway upregulation, OXPHOS inhibition results in failure to meet ATP demand and cell death.
  • Bottom Panel Quiescent cancer cells have low ATP demand but live in a highly compromised microenvironment (low glucose and hypoxia). Inhibition of OXPHOS is lethal as insufficient glucose is present to compensate for the loss of ATP production by oxidative phosphorylation.
  • Figure 8 is a diagram showing the conformational change undergone by elesclomol upon chelation with copper.
  • Figure 9 is a graph showing the synergy of elesclomol with PARP inhibitors.
  • drug sensitivity was assessed following treatment of mutant BRCA1 cells (SUM149) with elesclomol including paclitaxel (A) and PARP inhibitors talazoparib (B) and rucaparib (C).
  • A mutant BRCA1 cells
  • B PARP inhibitors talazoparib
  • C rucaparib
  • Figure 10 is a diagram showing gene screens indicating genes whose activity is affected by elesclomol: (A) Gene scores in elesclomol-1 (100 nM) and elesclomol-2 (1 ⁇ M) treated K562 cells. The gene score is the median log 2 fold change in abundance of all sgRNAs targeting that gene during the culture period.
  • Figure 17 is a series of graphs showing the effects of a 72-hour treatment with elesclomol on the viability of either the RMG1 NTC (non-targeted control) clear cell ovarian cancer cell line or the RMG1 ARID1A mutant cell line.
  • Figures 16 and 17 do show a clear difference in results between the ARID1A wild-type and the ARID1A mutant phenotype, the difference in results is not clear in Figure 18. This is simply an artifact of the assays.
  • the Incucyte analyses shown in Figure 18 are based on bright-field images which provide an analysis of confluence so does not differentiate between viable and dying cells, whereas Figures 16 and 17 measure only viable cells.
  • Figure 19 shows photomicrographs of either the OVCA429 NTC (non-targeted control) clear cell ovarian cancer cell line or the OVCA429 ARID1A mutant cell line that were either not treated with elesclomol or treated with 10 nM of elesclomol.
  • Figure 26 shows the results demonstrating that ARID1A-mutant cell lines are selectively sensitive to elesclomol in vitro under ambient (normoxic) conditions, with lesser effects shown under hypoxic conditions: panel (A) shows the ARID1A profile of OCCC cell lines (OVISE, OVMANA, RMG1, CAOV3, JHOC5, JHOC7, and JHOC9) shown by western blotting; panel (B) shows the IC50 for elesclomol on OCCC cell lines (OVISE, OVMANA, RMG1, JHOC5, and JHOC9) in a 72-hour MTT assay; panel (C) shows the ARID1A profile of RMG1 and JHOC5 cells (with wild-type ARID1A shown to the left and mutant ARID1A shown to the right for each cell line) by western blotting; panel (D) is a graph showing that the IC50 decreases for RMG1 and JHOC5 cells for mutant ARID1A (shown to the right for each cell
  • the terms “comprise,” “include,” and linguistic variations thereof denote the presence of recited features, elements, method steps, or other components of the invention without the exclusion of the presence of additional /recited features, elements, method steps, or other components.
  • the terms “consisting of” and linguistic variations thereof denote the presence of recited features, elements, method steps, or other components of the invention and exclude any unrecited recited features, elements, method steps, or other components of the invention except for ordinarily-associated impurities.
  • non-human mammals includes, but is not limited to, socially or economically important animals or animals used for research including cattle, sheep, goats, horses, pigs, llamas, alpacas, dogs, cats, rabbits, guinea pigs, rats, and mice.
  • methods and compositions according to the present invention are not limited to treatment of humans.
  • the term “patient” can used in place of “subject.”
  • PATENT EDISON-58717 [0073]
  • the terms “effective amount,” “therapeutically effective amount,” or other equivalent terminology refer to the amount of a compound or compounds or to the amount of a composition sufficient to effect beneficial or desired results.
  • Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs or other portions of the respiratory tract (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (such as, but not limited PATENT EDISON-58717 to, intravenously, subcutaneously, intraperitoneally, or by other injection routes as known in the art).
  • injection such as, but not limited PATENT EDISON-58717 to, intravenously, subcutaneously, intraperitoneally, or by other injection routes as known in the art).
  • the term “pharmaceutical composition” refers to the combination of one or more therapeutically active agents with at least one carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • pharmaceutically acceptable or “pharmacologically acceptable,” as used herein, refer to compositions, or components within compositions, that do not substantially produce adverse reactions, such as, but not limited to, toxic, allergic, or unwanted immunological reactions, when administered to a subject.
  • the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound that is used in a method of the present invention or is a component of a composition of the present invention, which, upon administration to a subject, is capable of providing a compound of the present invention or an active metabolite or residue thereof.
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids such as oxalic
  • bases include, but are not limited to, alkali metals (such as sodium or potassium) hydroxides, alkaline earth metals (such as calcium or magnesium), hydroxides, ammonia, and compounds of formula NW4 + , wherein W is C1-C4 alkyl, and the like.
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate
  • Such instructions for example, provide dosing, routes of administration, or decision trees for treating physicians for correlating patient- specific characteristics with therapeutic courses of action.
  • Such instructions may be part of a kit according to the present invention.
  • analogs and derivatives of the compounds described in further detail below including elesclomol and other therapeutically active agents described herein.
  • analog refers to a chemical compound that is structurally similar to a parent compound, but differs slightly in composition (e.g., one atom or functional group is different, added, or removed).
  • the analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity.
  • Derivatization may involve substitution of one or more moieties within the molecule (e.g., a change in functional group).
  • derivative also includes conjugates and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions).
  • alkyl refers to an unbranched, branched, or cyclic saturated hydrocarbyl residue, or a combination thereof, of from 1 to 12 carbon atoms, or in some cases up to 50 or more carbon atoms, that can be optionally substituted; the alkyl residues contain only C and H when unsubstituted.
  • the unbranched or branched saturated hydrocarbyl residue is from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, which is referred to herein as “lower alkyl.”
  • the alkyl residue is cyclic and includes a ring, it is understood that the hydrocarbyl residue includes at least three carbon atoms, which is the minimum number to form a ring.
  • An alkyl group can be linear, branched, cyclic, or a combination thereof, and may contain from 1 to 50 or more carbon atoms, such as a straight chain or branched C1-C20 alkane.
  • C x -C y when used in conjunction with a chemical moiety, such PATENT EDISON-58717 as alkyl, alkenyl, alkynyl, or carbocycle is meant to include groups that contain from x to y carbons in the chain or ring.
  • Cx-Cy alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, or other alternatives.
  • Cx-Cy alkenyl and Cx-Cy alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • C x -C y carbocycle refers to a substituted or unsubstituted carbocycle, that contain from x to y ring carbons.
  • branched alkyl refers to a chain of carbon and hydrogen atoms, without double or triple bonds, that contains a fork, branch, and/or split in the chain (e.g., 3,5-dimethyl-2-ethylhexane, 2-methyl-pentane, 1- methyl-cyclobutane, ortho-diethyl-cyclohexane, or other alternatives).
  • Branching refers to the divergence of a carbon chain
  • substitution refers to the presence of non-carbon/non- hydrogen atoms in a moiety.
  • carbocyclyl encompasses cycloalkyl.
  • the carbocyclic and heterocyclic structures encompass compounds having monocyclic, bicyclic or multiple (polycyclic) ring systems; and such systems may mix aromatic, heterocyclic, and carbocyclic rings. Mixed ring systems are described according to the ring that is attached to the rest of the compound being described.
  • Bicyclic or polycyclic rings may include fused or spiro rings.
  • Carbocycles may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic carbocycle e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • the PATENT EDISON-58717 carbocycle is an aromatic carbocycle .
  • the carbocycle is a cycloalkyl.
  • the carbocycle is a cycloalkenyl.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.
  • an alkenyl group can be optionally substituted by one or more substituents such as those substituents described herein.
  • a “non-aromatic carbocycle” includes rings and ring systems that are saturated, unsaturated, substituted or unsubstituted, but not aromatic or aryl rings or ring systems.
  • the term “cycloalkyl” refers to a completely saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups of the present application may range from three to ten carbons (C 3 to C 10 ).
  • a cycloalkyl group may be unsubstituted, substituted, branched, and/or unbranched.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or can be selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
  • the alkyl group containing the non-carbon substitution(s) may be a linear alkyl, branched alkyl, cycloalkyl (e.g., cycloheteroalkyl), or combinations thereof.
  • Non-carbons may be at terminal locations (e.g., 2-hexanol) or integral to an alkyl group (e.g., diethyl ether).
  • hetero terms refer to groups that typically contain 1-3 O, S or N heteroatoms or combinations thereof within the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the specified heteroatoms to form, respectively, a heteroalkyl, heteroalkenyl, or heteroalkynyl group. In some cases, more than three heteroatoms may be present.
  • the heteroalkyl group may be PATENT EDISON-58717 optionally substituted as described herein.
  • Representative heteroalkyl groups include, but are not limited to --OCH2OMe, --OCH2CH2OMe, or --OCH2CH2OCH2CH2NH2.
  • heteroalkylene refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a heteroatom, e.g., O, N or S, or another heteroatom as described above.
  • Heteroalkylene or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group.
  • heteroalkylene group may be optionally substituted as described herein.
  • Representative heteroalkylene groups include, but are not limited to --OCH2CH2O--, --OCH2CH2OCH2CH2O--, or --OCH2CH2OCH2CH2OCH2CH2O-- .
  • optionally substituted indicates that the particular group or groups referred to as optionally substituted may have no non-hydrogen substituents, or the group or groups may have one or more non-hydrogen substituents consistent with the chemistry and pharmacological activity of the resulting molecule and such that a stable compound is formed thereby, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, hydrolysis, lactone or lactam formation, or other reaction. If not otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present on the unsubstituted form of the group being described; fewer than the maximum number of such substituents may be present.
  • the group takes up two available valences on the carbon atom to which the optional substituent is attached, so the total number of substituents that may be included is reduced according to the number of available valences.
  • substituted whether used as part of “optionally substituted” or otherwise, when used to modify a specific group, moiety, or radical, means that one or more hydrogen atoms are, each, independently of each other, replaced with the same or different substituent or substituents.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds that do not significantly alter the pharmacological activity of the compound in the context of the present invention.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • aromatic rings include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo(c)thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, naphthalene, pyridine, quinolone, isoquinoline, pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, PATENT EDISON-58717 triazine (e.g., 1,2,3-triazine; 1,2,4-triazine; 1,3,5 triazine), and thiadiazole.
  • triazine e.g., 1,
  • any monocyclic or fused ring bicyclic system that has the characteristics of aromaticity in terms of delocalized electron distribution throughout the ring system is included in this definition.
  • This definition also includes bicyclic groups where at least the ring that is directly attached to the remainder of the molecule has the characteristics of aromaticity, including the delocalized electron distribution that is characteristic of aromaticity.
  • the ring systems contain 5 to 12 ring member atoms and up to four heteroatoms, wherein the heteroatoms are selected from the group consisting of N, O, and S.
  • the monocyclic heteroaryls contain 5 to 6 ring members and up to three heteroatoms selected from the group consisting of N, O, and S; frequently, the bicyclic heteroaryls contain 8 to 10 ring members and up to four heteroatoms selected from the group consisting of N, O, and S.
  • the number and placement of heteroatoms in heteroaryl ring structures is in accordance with the well-known limitations of aromaticity and stability, where stability requires the heteroaromatic group to be stable enough to be exposed to water at physiological temperatures without rapid degradation.
  • the term “hydroxyheteroaryl” refers to a heteroaryl group including one or more hydroxyl groups as substituents; as further detailed below, further substituents can be optionally included.
  • haloaryl and haloheteroaryl refer to aryl and heteroaryl groups, respectively, substituted with at least one PATENT EDISON-58717 halo group, where “halo” refers to a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included.
  • haloalkyl refers to alkyl, alkenyl, and alkynyl groups, respectively, substituted with at least one halo group
  • halo refers to a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included.
  • C1-C6 alkyl includes alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms and all possible subranges.
  • hydroxyaryl refers to an aryl group including one or more hydroxyl groups as substituents; as further detailed below, further substituents can be optionally included.
  • solvate means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound of the invention, with one or more solvent molecules.
  • solvate typically means a physical association of a compound involving varying degrees of ionic and/or covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent atoms are incorporated into the crystal lattice of the crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates. Suitable solvates in which the solvent is other than water include, but are not limited to, ethanolates or methanolates. When water is the solvent, the corresponding solvate is a “hydrate.” Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other hydrated forms.
  • the pharmaceutically acceptable salt and/or prodrug of compounds described herein for use in methods or compositions according to the present invention may also exist in a solvate form.
  • the solvate is a hydrate
  • the hydrate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the anhydrous compound of the present invention.
  • PATENT EDISON-58717 Additionally, compounds may exist as clathrates or other complexes, which are therapeutic agent-host inclusion complexes wherein the therapeutic agent and the host are present in stoichiometric or non-stoichiometric amounts.
  • ester means any ester of a present compound in which any of the --COOH functions of the molecule is replaced by a --COOR function, in which the R moiety of the ester is any carbon-containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof.
  • the hydrolyzable esters of the present compounds are the compounds whose carboxyls are present in the form of hydrolyzable ester groups.
  • esters are pharmaceutically acceptable and can be hydrolyzed to the corresponding carboxyl acid in vivo.
  • alkenyl refers to an unbranched, branched or cyclic hydrocarbyl residue having one or more carbon-carbon double bonds. Typically, the hydrocarbyl residue has from 2 to 12 carbon atoms (C 2 -C 12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl).
  • an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C 1 -C 3 alkylene).
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene).
  • an alkenylene comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkenylene). PATENT EDISON-58717 In other embodiments, an alkenylene comprises two carbon atom (i.e., C 2 alkenylene).
  • An alkenylene group can be optionally substituted by one or more substituents such as those substituents described herein.
  • alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkynylene comprises two to ten carbon atoms (i.e., C 2 -C 10 alkynylene).
  • alkenylene group can be optionally substituted by one or more substituents such as those substituents described herein.
  • substituents such as those substituents described herein.
  • the term “amine” or “amino” includes primary, secondary, and tertiary amines wherein each non-hydrogen group on nitrogen may be selected from alkyl, aryl, and the like. Amines include but are not limited to --NH 2 , --NH-phenyl, --NH--CH 3 , --NH-- CH2CH3, and --N(CH3)benzyl. The amino group can be optionally substituted.
  • acyl encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one of the two available valence positions of a carbonyl carbon atom
  • heteroacyl refers to the corresponding groups wherein at least one carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from N, O and S.
  • arylalkyl and “heteroarylalkyl” refer to aromatic and heteroaromatic ring systems which are bonded to their attachment point through a linking group such as an alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers. Typically the linker is C1-C8 alkyl. These linkers may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety.
  • An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group may be substituted with the same substituents described above for aryl groups.
  • an arylalkyl group includes a phenyl ring optionally substituted with the groups defined above for aryl groups and a C 1 -C 4 alkylene that is unsubstituted or is substituted with one or two C 1 -C 4 alkyl groups or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
  • a heteroarylalkyl group preferably includes a C 5 -C 6 monocyclic heteroaryl group that is optionally substituted with the groups described above as substituents typical on aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, or it includes an optionally substituted phenyl ring or C 5 -C 6 monocyclic heteroaryl and a C 1 -C 4 heteroalkylene that is unsubstituted or is substituted with one or two C 1 -C 4 alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
  • heteroatom refers to any atom that is not carbon or hydrogen, such as nitrogen, oxygen or sulfur. When it is part of the backbone or skeleton of a PATENT EDISON-58717 chain or ring, a heteroatom must be at least divalent, and will typically be selected from N, O, P, and S, more typically from N, O, and P.
  • heteroatom can include, in some contexts, other atoms, including selenium, silicon, or boron.
  • lower alkanoyl refers to an alkanoyl group in which the alkyl portion of the alkanoyl group is C1-C6.
  • the alkyl portion of the alkanoyl group can be optionally substituted as described above.
  • alkylcarbonyl can alternatively be used.
  • alkenylcarbonyl and alkynylcarbonyl refer to an alkenyl or alkynyl group, respectively, linked to a carbonyl group.
  • alkoxy refers to an alkyl group covalently linked to an oxygen atom; the alkyl group can be considered as replacing the hydrogen atom of a hydroxyl group.
  • lower alkoxy refers to an alkoxy group in which the alkyl portion of the alkoxy group is C1-C6.
  • the alkyl portion of the alkoxy group can be optionally substituted as described above.
  • haloalkoxy refers to an alkoxy group in which the alkyl portion is substituted with one or more halo groups.
  • sulfo refers to a sulfonic acid (—SO3H) substituent.
  • alkylaminoalkyl and “dialkylaminoalkyl” refer to groups of the structure —Alk1-NH-Alk2 and —Alk1-N(Alk2)(Alk3), wherein Alk1, Alk2, and Alk3 refer to alkyl groups as described above.
  • alkylsulfonyl refers to a group of the structure — S(O)2-Alk wherein Alk refers to an alkyl group as described above.
  • arylalkylsulfonyl refers to a group of the structure —S(O) 2 -AlkAr, where Alk is an alkyl group as described above and Ar is an aryl group as described above.
  • alkyloxycarbonyl refers to an ester substituent including an alkyl group wherein the carbonyl carbon is the point of attachment to the molecule.
  • An example is ethoxycarbonyl, which is CH 3 CH 2 OC(O)—.
  • alkenyloxycarbonyl refers to similar ester substituents including an alkenyl group, alkenyl group, or cycloalkyl group respectively.
  • aryloxycarbonyl refers to an ester substituent including an aryl group wherein the carbonyl carbon is the point of attachment to the molecule.
  • aryloxyalkylcarbonyl refers to an ester substituent including an alkyl group wherein the alkyl group is itself substituted by an aryloxy group.
  • the term “absent” when used in reference to a functional group or substituent, particularly in reference to the chemical structure of a compound, means that the particular functional group or substituent is not present in the compound being described.
  • the absence of the substituent typically means that the bond to the substituent is absent and that absence of the bond is compensated for with a H atom.
  • the absence of the position typically means that the two positions otherwise connected by the absent position are instead directly connected by a covalent bond.
  • thiocarbonyl and combinations of substituents including “thiocarbonyl” include a carbonyl group in which a double-bonded sulfur replaces the normal double-bonded oxygen in the group.
  • alkylidene and similar terminology refer to an alkyl group, alkenyl group, alkynyl group, or cycloalkyl group, as specified, that has two hydrogen atoms removed from a single carbon atom so that the group is double-bonded to the remainder of the structure.
  • PATENT EDISON-58717 Certain compounds described herein for use in methods and compositions according to the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention unless specific isomers are excluded.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the term “tautomer,” as used herein, refers to one of two or more structural isomers that exist in equilibrium and that are readily converted from one form to another. Examples of tautomerism include, but are not limited to, keto-enol tautomerism, enamine-imine tautomerism, and lactam-lactim tautomerism.
  • Elesclomol (N′ 1 ,N′ 3 -dimethyl-bis(phenylcarbonothioyl)propanedihydrazide) is a novel, injectable, drug candidate that kills cancer cells by elevating oxidative stress levels beyond a breaking point, triggering programmed cell death. In preclinical models elesclomol showed potent killing of a broad range of cancer cell types at high doses, and an ability to strongly enhance the efficacy of certain chemotherapy agents, with minimal additional toxicity, at moderate doses.
  • Elesclomol induces oxidative stress by provoking a buildup of reactive oxygen species within cancer cells (J.R. Kirshner et al., “Elesclomol Induces Cancer Cell Apoptosis Through Oxidative Stress,” Mol. Cancer Ther. 7: 2319-2327 (2008)). Elesclomol requires a redox-active metal ion to function.
  • the Cu(II) complex is 34 times more potent than the Ni(II) complex and 1040-fold more potent than the Pt(II) complex (A.A.
  • Elesclomol can also directly or indirectly induce apoptosis. Elesclomol can also act as an oxidative phosphorylation inhibitor (A.P. Nayak et al., “Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies against Ovarian Cancer,” Cancers (Basel) 10: 337 (2018)). [0122] Elesclomol is an anticancer drug that targets mitochondrial metabolism.
  • OCCC Compared to HGSOC, treatment for OCCC has not benefited from recent advances in treatment strategies.
  • OCCC is often detected at an early stage, presenting with a large unilateral pelvic mass confined to the ovary and causing symptoms of abdominal pain and distortion. Despite the earlier diagnosis, OCCC exhibits poorer survival compared to HGSOC across all FIGO stages. When diagnosed at an advanced stage, OCCC exhibits the worst prognosis and lowest survival rates among all OEC subtypes.
  • ARID1A mutations result in cells that are highly susceptible to synthetic lethality by agents that interrupt OXPHOS or the mitochondrial electron transport chain (mETC).
  • OCCC patients generally do not have BRCA mutations and thus are not considered to be within the treatment scope of recent FDA-approved PARP inhibitors. Therefore, at present, the extremely poor prognosis and lack of an effective systemic therapy for OCCC remains a significant unmet medical need, especially when surgical cytoreduction is insufficient.
  • BRCA mutations occur at a very low frequency in OCCC (Arts-de-Jong, 2016) and mutations in TP53 occur much less frequently compared to other OECs (Ho, 2001) highlighting important differences in these OEC histological subtypes.
  • the most frequent mutations observed in OCCC include ARID1A and PIK3CA (Kwan 2015).
  • FIG. 3(A) shows the impact of ARID1A loss, determined via mutation, homozygous deletion, or loss of expression, and survival in TCGA serous ovarian cancers.
  • Figure 3(B) shows the progression-free survival of relapsed, platinum-sensitive, high- grade ovarian carcinomas in a clinical trial of rucaparib (a PARP inhibitor), stratified based on ARID1A mutation status.
  • ROS reactive oxygen species
  • GSH is an antioxidant involved in scavenging ROS and detoxifying the cell to promote cancer progression by avoiding activation of cell-death signaling pathways.
  • GSH depletion has been largely unsuccessful as a therapeutic strategy.
  • cells with GSH abnormalities could be susceptible to synthetic lethality.
  • Conditions of oxidative stress e.g. high ROS
  • GSSG accumulation can be potentially toxic and can result in activation of redox mediated cell death (Couto, 2016) and therefore is rapidly converted back to the reduced form (GSH) by NADPH highlighting the dependence on oxidative phosphorylation.
  • ARID1A mutated cells have been demonstrated to be significantly more sensitive to inhibition of OXPHOS versus wild-type cells (Emmings, 2019).
  • FIG. 6 shows the difference between cells with ARID1A mutations and cells with active ARID1A in terms of the effect of accumulation of ROS:
  • A ARID1A complex associated with NRF2 in high ROS environment promotes transcription of SLC7A11 and increased cystine uptake and activation of GHS antioxidant pathway.
  • B Loss of ARID1A PATENT EDISON-58717 inhibits cystine uptake resulting in reduced antioxidant capacity within the cell and increased susceptibility to ROS-driven cell death.
  • High ROS accumulation has different effects on cell fate depending on p53 status; with more apoptosis in cells with functional WTp53 (Lyu, 2016). In cells with intact TP53, this phenomenon tips the balance toward apoptotic pathways.
  • mutant p53 cancer cells decrease expression of detoxifying enzymes to potentiate aberrant signaling and uncontrolled tumor growth whereas intact p53 tips the balance toward cell death.
  • Exploiting this vulnerability in reliance on OXPHOS, by interrupting or uncoupling members of the mitochondrial electron transport chain, for example, would be a viable strategy of synthetic lethality. Selecting patients whose tumors express vulnerabilities rendering them susceptible to synthetic lethality is of critical importance. Such a strategy would be expected to be particularly effective in tumors such as OCCC which express ARID1A mutations and are generally devoid of mutations in TP53, thereby providing a novel therapeutic strategy against these underserved tumors.
  • Figure 7 shows a therapeutic window for cancer cells in the presence of an oxidative phosphorylation (OXPHOS) inhibitor.
  • OXPHOS oxidative phosphorylation
  • Top Panel Normal body cells have moderate ATP demand and adequate levels of oxygen and glucose and survive in presence of OXPHOS inhibitors by upregulating glycolysis to meet their ATP demands.
  • Middle Panel Highly proliferating cancer cells have extraordinarily high ATP demand and adequate levels of oxygen and glucose. Despite glycolytic pathway upregulation, OXPHOS inhibition results in failure to meet ATP demand and cell death.
  • Quiescent cancer cells have low ATP demand but live in a highly compromised microenvironment (low glucose and hypoxia).
  • elesclomol Upon chelation with copper in the blood stream, elesclomol undergoes a conformational change allowing the drug to permeate cellular and sub-cellular membranes. As stated above, elesclomol can also bind other divalent metal ions. This conformational change is shown in Figure 8. [0149] Previously, it was believed that elesclomol induces apoptosis in cancer cells through a non-specific induction of oxidative stress, possibly through the generation of reactive oxygen species (ROS) due to cycling of Cu(II) ⁇ Cu(I). However, comparison of elesclomol to over 3000 drug profiles demonstrated that the elesclomol profile was unique suggesting that elesclomol acts by a novel mechanism not shared by other tested compounds.
  • ROS reactive oxygen species
  • elesclomol inhibits electron transport activity in isolated, intact mammalian mitochondria, and induces a dose-dependent inhibition of mitochondrial NADH-ubiquinone oxidoreductase activity (complex I).
  • CRISPR/CAS9-based screening identified ferredoxin 1 (FDX1), a mitochondrial enzyme critical to the iron-sulfur (Fe-S) biosynthesis pathway, as the single protein target of the elesclomol. In both screens, this gene scored higher than any other gene. Elesclomol-Cu directly binds and inhibits FDX-1 function to block iron-sulfur cluster formation in complex I, a critical component of the mitochondrial electron transport chain.
  • FIG. 10 The results of these gene screens are shown in Figure 10.
  • Complex I plays a role in redox control and the biosynthesis of macromolecules and nucleic acids necessary for cell proliferation. It is suggested that these complex I-dependent events contribute to tumor formation, resistance to cell death, and metastasis of cancer cells in part by causing an increase in ROS levels.
  • FIG. 11 shows that elesclomol inhibits the natural function of FDX1 in FE-S cluster biosynthesis.
  • the [2Fe–2S] cluster in FDX1 is indicated by spheres.
  • Tumors such as OCCC with high prevalence of inactivating mutations in the ARID1A subunit of SWI/SNF complex may represent an ideal biomarker-derived population for targeted therapy with elesclomol. These tumors would have a profound dependency on OXPHOS compared to wild type cells revealing a valuable therapeutic target for elesclomol- driven synthetic lethality in an area of significant unmet medical need.
  • FIG. 13 is a diagram showing that ARID1A-mutant tumors are highly dependent on OXPHOS offering a potential strategy for synthetic lethality employing targeted agents interrupting mitochondrial metabolism.
  • FIG. 14 is a diagram showing that the protein target of elesclomol is ferredoxin- 1, a key component of the OXPHOS pathway establishing a synthetically lethal therapeutic strategy in ARID1A-mutant tumors.
  • the preclinical pharmacokinetics, distribution, metabolism and toxicity of elesclomol has been well established based on a series of nonclinical, Good Laboratory Practices (GLP)-compliant safety assessment studies. In general, elesclomol (in combination with paclitaxel and/or paclitaxel + carboplatin) was well-tolerated and the pharmacokinetics of elesclomol were consistent across trials.
  • GLP Good Laboratory Practices
  • FIG. 15 shows the occurrence of ARID1A mutations in a number of types of malignancies, including mutations, deletions, amplification, and multiple alterations.
  • ARID1A loss is also associated with treatment resistance and poor patient outcomes in a range of tumors including HER2 + breast cancer. Recently published findings suggest that tumors accumulate ARID1A mutations in response to treatment as a mechanism of acquired resistance. Such tumors may be susceptible to synthetic lethality treatment strategies with elesclomol.
  • elesclomol can be employed as either the free acid or as a salt, typically a sodium salt. However, also, as detailed further below, elesclomol is typically employed as a coordinate covalent complex with a divalent transition state metal ion.
  • Elesclomol is one of a number of therapeutic agents that is considered an agent that has previously been considered one of suboptimal importance.
  • the present invention describes novel improvements, pharmaceutical ingredients, dosage forms, excipients, solvents, diluents, drug delivery systems, preservatives, more accurate drug administrations, improved dose determination and schedules, toxicity monitoring and amelioration, techniques or agents to circumvent or reduce toxicity, and techniques and tools to identify/predict those patients who might have a better outcome with a therapeutic agent by the use of phenotype or genotype determination through the use of diagnostic kits or pharmacokinetic or metabolism monitoring approaches.
  • the present invention also relates to the use of drug delivery systems, novel prodrugs, polymer conjugates, novel routes of administration, other agents to potentiate the activity of the compounds or inhibit the repair of suboptimal cellular effects or sublethal damage or to “push” the cell into more destructive cellular phases such as immune stimulation and apoptosis.
  • these suboptimal therapeutics in conjunction with radiation PATENT EDISON-58717 or other conventional chemotherapeutic agents or biotherapeutic agents such as antibodies, vaccines, cytokines, lymphokines, gene and antisense RNA therapies, as detailed further below, would provide novel approaches and potential significant treatment improvement.
  • suboptimal therapy includes agents where Phase I toxicity precluded further human clinical evaluation. It also includes those agents from Phase II trials where limited (e.g., ⁇ 25% response rates) or no significant treatment responses were identified. Also, suboptimal therapy includes those agents, the subject of Phase III clinical trials the outcome of which was either medically or statistically not significant to warrant regulatory submission or approval by government agencies for commercialization for commercialized agents whose clinical performance (i.e. response rates) as a monotherapy are less than 25%, or whose side effects are severe enough to limit wide utility.
  • compositions according to the present invention are of particular utility in the treatment of OCCC wherein the OCCC has metastasized, including, but not limited to, OCCC wherein the metastasis has occurred in an organ selected from the lung, the stomach, and the brain.
  • Dose Modification Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations to the time that the compound is administered, the use of dose-modifying agents that control the rate of metabolism of the compound, normal tissue protective agents, or other relevant factors affecting dosages.
  • infusion schedules e.g., bolus i.v. versus continuous infusion
  • intermittent infusions for 1-3, 3-6, 6-12, or 12-24 hours
  • suitable dosages in conjunction with the use of lymphokines e.g., G- PATENT EDISON-58717 CSF, GM-CSF, EPO
  • rescue agents such as leucovorin for 5-FU or thiosulfate for cisplatin treatment.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: i.v. infusion for hours to days; biweekly, triweekly, monthly administration; doses greater than 100 mg/m 2 /day; progressive escalation of dosing from 100 mg/m 2 /day based on patient tolerance; doses less than 2 mg/m 2 for greater than 14 days; modification of dosage in conjunction with use of polyamine to modulate metabolism; modification of dosage in conjunction with use of eflornithine to modulate metabolism; selected and intermittent boost dose administration; bolus single and multiple doses escalating from 100 mg/m 2 ; oral doses below 30 or above 130 mg/m 2 .
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the route that the compound is administered.
  • General examples include: changing the route of administration from oral to intravenous administration and vice versa, or the use of specialized routes such as subcutaneous, intramuscular, intraarterial, intraperitoneal, intralesional, intralymphatic, intratumoral, intrathecal, intravesicular, or intracranial administration.
  • Schedule of Administration [0183] Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations to the time that the compound is administered. General examples include: changing from a monthly administration to a weekly or daily dosing or variations of the schedule.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: daily; weekly for three weeks; weekly for two PATENT EDISON-58717 weeks; biweekly; biweekly for three weeks with a 1-2 week rest period; intermittent boost dose administration; daily for one week then once per week for multiple weeks; daily on days 1-5, 8- 12 every three weeks; or daily on days 1-3, 8-11 per cycle.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations to the type of patient that would best tolerate or benefit from the use of the compound.
  • General examples include: use of pediatric doses for elderly patients, altered doses for obese patients; exploitation of co-morbid disease conditions such as diabetes, cirrhosis, or other conditions that may uniquely exploit a feature of the compound.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • patients with disease conditions with high levels of metabolic enzymes, reactive oxygen species, histone deacetylase, protein kinases, or ornithine decarboxylase include: patients with disease conditions with high levels of metabolic enzymes, reactive oxygen species, histone deacetylase, protein kinases, or ornithine decarboxylase; patients with disease conditions with low levels of metabolic enzymes, histone deacetylase, protein kinases, or ornithine decarboxylase; patients with low or high susceptibility to thrombocytopenia or neutropenia; patients intolerant of GI toxicities; patients with deficiencies in DNA repair capacity including BRCA, ARID1A or other deficiencies in the SWI/SWF pathway or mitochondrial electron transport, over- or under- expression of jun, GPCR’s and signal transduction proteins, VEGF, prostate specific genes, protein
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by more precise identification of a patient’s ability to tolerate, metabolize and exploit the use of the compound.
  • General examples include: use of diagnostic tools and kits to better characterize a patients ability to process/metabolize a chemotherapeutic agent or their susceptibility to toxicity caused by potential specialized cellular, metabolic, organ system phenotypes.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • diagnostic tools, techniques, kits and assays to confirm a patient’s particular phenotype and for the measurement of metabolism enzymes and metabolites PATENT EDISON-58717 histone deacetylase, protein kinases, ornithine decarboxylase, VEGF, products of prostate specific genes, telomerase, jun GPCR’s; ARID1A mutant phenotype; surrogate compound dosing; or low dose drug pre-testing for enzymatic status.
  • the gene ARID1A is a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes.
  • the encoded protein is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. It possesses at least two conserved domains that could be important for its function. First, it has an ARID domain, which is a DNA- binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SWI/SNF complex at the beta-globin locus.
  • the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SWI/SNF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. This gene has been commonly found mutated in gastric cancers, ovarian clear cell carcinoma, and pancreatic cancer. In breast cancer distant metastases acquire inactivation mutations in ARID1A not seen in the primary tumor, and reduced ARID1A expression confers resistance to different drugs such as trastuzumab and mTOR inhibitors.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by specialized preparation of a patient prior to or after the use of a therapeutic agent.
  • General examples include: induction or inhibition of metabolizing enzymes, specific protection of sensitive normal tissues or organ systems.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: use of colchicine or analogs; use of diuretics such as probenecid; use of uricase; non- oral use of nicotinamide; use of sustained release forms of nicotinamide; use of inhibitors of polyADP ribose polymerase; use of caffeine; leucovorin rescue; infection control; use of antihypertensives; alteration of stem cell populations; pretreatment to limit or prevent graft vs. host (GVH) cytokine storm reactions; use of anti-inflammatories; anaphylactic reaction suppression.
  • GVH graft vs. host
  • Toxicity Management Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by use of additional drugs or procedures to prevent or reduce potential side effects or toxicities.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by use of additional drugs or procedures to prevent or reduce potential side effects or toxicities.
  • General examples include: the use of anti-emetics, anti-nausea, hematological support agents to limit or prevent neutropenia, anemia, thrombocytopenia, vitamins, antidepressants, treatments for sexual dysfunction, or other agents or regimens known in the art.
  • Drug Combinations [0198] Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting unique drug combinations that may provide a more than additive or synergistic improvement in efficacy or side-effect management.
  • alkylating agents with anti-metabolites topoisomerase inhibitors with antitubulin agents.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol include: use with topoisomerase inhibitors; use with fraudulent nucleosides; use with fraudulent nucleotides; use with thymidylate synthetase PATENT EDISON-58717 inhibitors; use with signal transduction inhibitors; use with cisplatin or gallium analogs; use with alkylating agents such as the nitrosoureas (BCNU, Gliadel wafers, CCNU); use with bendamustine (Treanda); use with anti-tubulin agents; use with antimetabolites; use with berberine; apigenin; amonafide; colchicine and analogs; genistein; etoposide; cytarabine; camptothecin
  • Chemosensitization Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting them as chemosensitizers where no measurable activity is observed when used alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting them as chemosensitizers where no measurable activity is observed when used alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting them as chemosensitizers where no measurable activity is observed when used
  • Chemopotentiation Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting them as chemopotentiators where minimal therapeutic activity is observed alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting them as chemopotentiators where minimal therapeutic activity is observed alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed.
  • General examples include: amonafide with cisplatin or 5-FU.
  • inventive examples for redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol include: as a chemopotentiator in combination with topoisomerase inhibitors; use with fraudulent nucleosides; use with fraudulent nucleotides; use with thymidylate synthetase inhibitors; use with signal transduction inhibitors; use with cisplatin or gallium analogs; use with alkylating agents such as BCNU, BCNU wafers, Gliadel, bendamustine (Treanda); use with anti-tubulin agents; use with antimetabolites; use with berberine; apigenin; amonafide; colchicine and analogs; genistein; etoposide; cytarabine; camptothecins; vinca alkaloids; topoisomerase inhibitors; 5-fluorouracil; curcumin; NF-
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by drugs, treatments and diagnostics to allow for the maximum benefit to patients treated with a compound.
  • General examples include: pain management, nutritional support, anti-emetics, anti- nausea therapies, anti-anemia therapy, anti-inflammatories.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: use with therapies associated with pain management; nutritional support; anti-emetics; anti-nausea therapies; anti-anemia therapy; anti-inflammatories: antipyretics; immune stimulants; anti diarrhea medicines, famotidine, antihistamines, suppository lubricants, soothing agents, lidocaine, hydrocortisone.
  • NF- ⁇ B inhibitors such as parthenolide, curcumin, rosmarinic acid
  • natural anti-inflammatories including rhein, parthenolide
  • immunostimulants such as those found in PATENT EDISON-58717 Echinacea
  • antimicrobials such as berberine
  • flavonoids and flavones such as apigenenin, geni
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the pharmaceutical bulk substance.
  • General examples include: salt formation, homogeneous crystalline structure, pure isomers.
  • Specific inventive examples for redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol include: salt formation; homogeneous crystalline structure; pure isomers; increased purity; lower residual solvents and heavy metals.
  • Diluent Systems Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the diluents used to solubilize and deliver/present the compound for administration.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the diluents used to solubilize and deliver/present the compound for administration.
  • General examples include: Cremophor-EL, cyclodextrins for poorly water soluble compounds.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: use of emulsions; DMSO; NMF; DMF; DMA; ethanol; benzyl alcohol; dextrose-containing water for injection; Cremophor; cyclodextrins; PEG; a sweetening agent such as saccharin; agents to thicken an oral dosage form such as glycerol; taste masking effectors such as menthol, rum flavor, fruit flavorings.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the solvents used or required to solubilize a compound for administration or for further dilution.
  • General examples include: ethanol, dimethylacetamide (DMA).
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: the use of emulsions; dimethyl sulfoxide (DMSO); N-methylformamide (NMF); dimethylformamide (DMF); dimethylacetamide (DMA); ethanol; benzyl alcohol; dextrose-containing water for injection; Cremophor; PEG; glycerol, cocoa butter for suppositories.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: the use of mannitol; albumin; EDTA; sodium bisulfite; benzyl alcohol; carbonate buffers; phosphate buffers; glycerol; sweeteners; taste masking agents such as rum flavor, menthol; substituted celluloses; sodium azide as a preservative.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • Dosage Kits and Packaging Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the dosage forms, container/closure systems, accuracy of mixing and dosage preparation and presentation.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations in the dosage forms, container/closure systems, accuracy of mixing and dosage preparation and presentation.
  • General examples include: amber vials to protect from light, stoppers with specialized coatings.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: the use of amber vials to protect from light; stoppers with specialized coatings to improve shelf-life stability; special dropper measuring devices; single-use or multiple-use container closure PATENT EDISON-58717 systems; testing for allergies; suppository delivery devices, epinephrine pens for side effect management; physician and nurse assistance gloves; dosage measuring devices.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by the use of delivery systems to improve the potential attributes of a pharmaceutical product such as convenience, duration of effect, reduction of toxicities.
  • General examples include: nanocrystals, bioerodible polymers, liposomes, slow release injectable gels, microspheres.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: the use of nanocrystals; bioerodible polymers; liposomes; slow release injectable gels; microspheres; suspensions with glycerol, meltable drug release suppositories with polymers such as cocoa butter alone or in combination with PEG, lecithin; polylactide/polyglycolide; rectal plugs for drug delivery.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations to the parent molecule with covalent, ionic, or hydrogen bonded moieties to alter the efficacy, toxicity, pharmacokinetics, metabolism, or route of administration.
  • General examples include: polymer systems such as polyethylene glycols, polylactides, polyglycolides, amino acids, peptides, multivalent linkers.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • polymer systems such as polyethylene glycols; polylactides; polyglycolides; amino acids; peptides; multivalent linkers.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations to the parent structure of a molecule with additional chemical functionalities that may alter efficacy or reduce toxicity, pharmacological performance, route of administration, or other factors that alter efficacy or reduce toxicity.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • General examples include: alteration of side chains to increase or decrease lipophilicity, additional chemical functionalities to alter reactivity, PATENT EDISON-58717 electron affinity, binding capacity, salt forms.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol include: alteration of side chains to increase or decrease lipophilicity; additional chemical functionalities to alter reactivity; alteration of electron affinity; alteration of binding capacity; salt forms.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by alterations to the molecule such that improved pharmaceutical performance is gained with a variant of the active molecule in that after introduction into the body a portion of the molecule is cleaved to reveal the preferred active molecule.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • General examples include: enzyme sensitive esters, dimers, Schiff bases.
  • General examples include: inhibitors of multi-drug resistance, specific drug resistance inhibitors, specific inhibitors of selective enzymes, signal transduction inhibitors, repair inhibition.
  • Specific inventive examples for redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol include: the use of inhibitors of multi-drug resistance; specific drug resistance inhibitors; specific inhibitors of selective enzymes; signal transduction inhibitors; repair inhibition; topoisomerase inhibitors with non-overlapping side effects.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol
  • redox modulating agents include: the use against tumors resistant to the effects of biological response modifiers; cytokines; lymphokines; therapeutic antibodies; antisense therapies such as bevacizumab, trastuzumab, rituximab, and cetuximab; gene therapies; ribozymes; RNA interference.
  • Radiation Therapy Enhancement Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting their use in combination with ionizing radiation, phototherapies, heat therapies, radio- frequency generated therapies.
  • redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by exploiting their use in combination with ionizing radiation, phototherapies, heat therapies, radio- frequency generated therapies.
  • General examples include: hypoxic cell sensitizers, radiation sensitizers/protectors, photosensitizers, radiation repair inhibitors.
  • Improvements for suboptimal therapeutics including redox modulating agents such as elesclomol or derivatives, analogs, salts, solvates, or prodrugs of elesclomol are made by optimizing their utility by determining the various mechanisms of actions, biological targets of a compound for greater understanding and precision to better exploit the utility of the molecule.
  • General examples include: Gleevec for chronic myelocytic leukemia (CML), arsenic trioxide for acute promyelocytic leukemia (APL), retinoic acid for APL.
  • Yet another aspect of the present invention is induction of synthetic lethality by administration of elesclomol or a derivative or analog of elesclomol to a malignancy PATENT EDISON-58717 characterized by a mutation in ARID1A or in a component of the SWI/SNF complex wherein the elesclomol or the derivative or analog of elesclomol renders the malignant cells susceptible to a targeted agent that otherwise would have no effect.
  • transition metal cation is preferably divalent, such as, but not limited to, Ni 2+ , Cu 2+ , Co 2+ , Fe 2+ , Zn 2+ , Pt 2+ , and Pd 2+ .
  • the divalent transition metal cation is Cu 2+ or Ni +2 . Still more preferably, the divalent transition metal cation is Cu 2+ .
  • the molar ratio of elesclomol to the transition metal cation is equal to or greater than 0.5 and equal to or less than 2.0; typically, the molar ratio of elesclomol to the transition metal cation is 1.0.
  • PATENT EDISON-58717 A coordinate-covalent complex of elesclomol and divalent copper is shown in Formula (II): (II).
  • a coordinate-covalent complex of elesclomol and divalent nickel is shown in Formula (III): .
  • Y is a covalent bond or –C(R 7 R 8 )--.
  • a particular derivative or analog of elesclomol is a compound of Formula (V): (V).
  • Additional derivatives or analogs of elesclomol are compounds of Formulas (VI) and (VII): S O PATENT EDISON-58717 (VI); and O O H H N N (VII).
  • Additional derivatives and analogs of elesclomol are compounds of Formula (VIII): (VIII), wherein: (1) each Z is independently S, O, or Se, provided that both Z moieties cannot be O; (2) R 1 and R 2 are each independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclic group wherein the heterocyclic group is bonded to the thiocarbonyl via a carbon-carbon linkage, an optionally substituted phenyl, an optionally substituted bicyclic aryl, an optionally substituted five-membered to seven-membered monocyclic heteroaryl, an optionally substituted nine-membered to fourteen-membered bicyclic heteroaryl wherein the heteroaryl is bonded to the thiocarbonyl via a carbon-carbon linkage,
  • the term “therapeutically effective quantity” or equivalent terminology refers to the quantity of a therapeutic agent in which a beneficial clinical outcome is achieved when the quantity of the therapeutic agent is administered to a subject in need thereof.
  • beneficial clinical outcome refers to a detectable or observable improvement in a clinical parameter as a result of the administration of the therapeutic agent; the detectable or observable improvement can be objective or subjective.
  • a “beneficial clinical outcome” can include, but is not necessarily limited to: a reduction in tumor mass or tumor burden; a reduction in tumor spread or metastasis; a reduction in pain; a reduction of symptoms associated with the malignancy such as seizures for central nervous system malignancies; a reduction of fatigue; a reduction of malaise; an increase in longevity; or an improved Karnofsky performance score.
  • Other determinants of a beneficial clinical outcome are known in the art, including determinants for diseases or conditions other than malignancies.
  • the therapeutically effective quantity will depend on the type and severity of the malignancy and on the characteristics of the subject, such as the general health, the age, the sex, the body weight, the tolerance to drugs, the relevant pharmacokinetic factors such as liver and kidney function.
  • the therapeutically effective quantity will also depend on other therapeutic agents being concurrently administered to the subject to treat the malignancy or to treat other co-morbid conditions affecting the subject.
  • One of ordinary skill in the art will be able to determine the therapeutically effective quantity based on this and other factors.
  • the therapeutically effective quantity typically ranges between about 1 mg/mm 2 /day to about 10 g/mm 2 /day; more typically, the therapeutically effective quantity ranges between about 2 mg/mm 2 /day to about 5 g/mm 2 /day. In some alternatives, the therapeutically effective quantity is from about 1 ⁇ g/kg to about 500 mg/kg, from about 500 ⁇ g/kg to about 250 mg/kg, from about 1 mg/kg to about 100 mg/kg, or from about 10 mg/kg to about 50 mg/kg.
  • co-administration and “co- administering” refer to the administration of at least two agents, such as elesclomol or a derivative, analog, or prodrug of elesclomol and an inhibitor, or therapies to a subject.
  • the co-administration of two or more agents or therapies is concurrent.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • the appropriate dosage for co-administration can be readily determined by one skilled in the art.
  • the respective agents or therapies are administered at lower dosages than appropriate for their administration alone.
  • co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful agent or agent, and/or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent.
  • concurrent administration refers to the administration of two or more active agents sufficiently close in time to achieve a combined therapeutic effect that is preferably greater than that which would be achieved by the administration of either agent alone.
  • Such concurrent administration can be carried out simultaneously, e.g., by administering the active agents together in a common pharmaceutically acceptable carrier, thereby forming a pharmaceutical composition with two or more active agents, in one or more doses of the pharmaceutical composition.
  • the malignancy to be treated can be, but is not limited to, ovarian epithelial cancer (OEC), ovarian clear-cell carcinoma (OCCC), uterine corpus endothelial carcinoma, stomach adenocarcinoma, bladder urothelial carcinoma, adenoid cystic carcinoma, uterine carcinosarcoma, cholangiocarcinoma, pancreatic cancer, metastatic esophagogastric cancer, recurrent or metastatic head and neck cancer, or lymphoid diffuse large B-cell lymphoma.
  • OEC ovarian epithelial cancer
  • OCCC ovarian clear-cell carcinoma
  • uterine corpus endothelial carcinoma stomach adenocarcinoma
  • bladder urothelial carcinoma adenoid cystic carcinoma
  • adenoid cystic carcinoma uterine carcinosarcoma
  • cholangiocarcinoma pancreatic cancer
  • metastatic esophagogastric cancer recurrent or meta
  • malignancies include, but are not limited to: fibrosarcoma; myxosarcoma; liposarcoma, chondrosarcoma; osteogenic sarcoma; chordoma; angiosarcoma; endotheliosarcoma; lymphangiosarcoma; lymphangioendotheliosarcoma; synovioma; mesothelioma; Ewing’s tumor; leiomyosarcoma; rhabdomyosarcoma; colon carcinoma, including Kras-mutated colon carcinoma; colorectal cancer; anal carcinoma; esophageal cancer; gastric cancer; hepatocellular cancer; bladder cancer; endometrial cancer; pancreatic cancer; breast cancer, including triple- negative breast cancer; ovarian cancer; prostate cancer; stomach cancer; atrial myxomas; squamous cell carcinoma; basal cell carcinoma; adenocarcinoma; sweat gland carcinoma; sebaceous gland carcinoma; thyroid and parathyroid
  • microtubulin stabilizers refers to an agent, typically an anti-cancer agent, that acts by arresting cells in the G2/M phase of cell division by stabilization of microtubules. Elesclomol or derivatives or analogs of elesclomol as described herein can contribute to the G2/M arrest associated with microtubulin stabilizers or agents with similar mechanisms of action.
  • microtubulin stabilizers include paclitaxel and paclitaxel analogs. Additional examples of microtubulin stabilizers include, but are not limited to: discodermolide; epothilone A; epothilone B; epothilone C; epothilone D; epothilone E; epothilone F; epothilone B N-oxide; epothilone A N-oxide; 16-aza-epothilone B; 21-aminoepothilone B; 21-hydroxyepothilone D; 26-fluoroepothilone; sagopilone; ixabepilone; uditelone; (1R,2S,4S,7S,8S,9S,10R,11S,12S,13R,17R,18S)-8,10-dihydroxy-1,5,9,18- tetramethyl-16,20-dioxahexacyclo[15
  • PATENT EDISON-58717 P-I.
  • Many analogs and derivatives of paclitaxel are known. These compounds have the basic taxane skeleton as a common structural feature and have the ability to arrest cells in the G2/M phase of the cell cycle due to microtubule stabilization. A wide variety of substituents can be made on the taxane skeleton while retaining the microtubule-stabilizing activity. It is also the case that zero, one, or two of the cyclohexane rings of a paclitaxel analog can have a double bond (paclitaxel itself has one double bond in such a six-membered ring).
  • paclitaxel analogs useful in methods or compositions according to the present invention are represented by Formulas (P-II) or (P-III): II); .
  • R10 is substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl; -- SR 19 , --NHR 19 , or –OR 19 ;
  • R11 is substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl;
  • PATENT EDISON-58717 (3)
  • R 12 is hydrogen, hydroxyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, --O-C(O)-(lower alkyl)--, --O-C(O)-(substituted lower alkyl)--, --O- CH2-O-(lower alkyl), or --S-CH2-O-(lower alkyl);
  • R 13 is hydrogen, methyl, or, taken together with R 14 , --CH 2 --;
  • R14 is hydrogen, hydroxyl
  • Paclitaxel analogs or derivatives can also be covalently linked to a pharmaceutically acceptable polymer such as a polyacrylamide.
  • Paclitaxel analogs and derivatives are disclosed in PCT Patent Application Publication No. WO 2010/065512 by Jiang et al.
  • microtubulin inhibitor refers to an anti-cancer agent that acts by inhibiting tubulin polymerization or microtubule assembly.
  • microtubulin inhibitors include, but are not limited to: erbulozole; dolastatin 10; mivobulin isethionate; vincristine; vinblastine; vinorelbine; vinflunine; vindesine; N-[[4-(5- bromopyrimidin-2-yl)oxy-3-methylphenyl]carbamoyl]-2-(dimethylamino)benzamide (NSC- 639829); N-[2-(4-hydroxyanilino)pyridin-3-yl]-4-methoxybenzenesulfonamide (ABT-751); estrogenhytin A; estrogenhytin C; spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, PATENT EDISON-58717 spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, spongistatin 9; cemadotin hydrochloride;
  • PATENT EDISON-58717 Other microtubule-disrupting antineoplastics include, but are not necessarily limited to, cabazitaxel, larotaxel, vedotin, belantamab mafodotin, ortataxel, and tesetaxel.
  • a second category of suitable additional therapeutic agents is PARP inhibitors. Inhibitors of the enzyme poly-ADP ribose polymerase (PARP) have been developed for multiple indications, especially for treatment of malignancies. Several forms of cancer are more dependent on the activity of PARP than are non-malignant cells.
  • PARP poly-ADP ribose polymerase
  • the enzyme PARP catalyzes the polymerization of poly-ADP ribose chains, typically attached to a single-strand break in cellular DNA.
  • the coenzyme NAD + is required as a substrate for generating ADP-ribose monomers to be polymerized;
  • nicotinamide is the leaving group during polymerization, in contrast to pyrophosphate which is the leaving group during normal DNA or RNA synthesis, which leaves a pyrophosphate as the linking group between adjacent ribose sugars in the chain rather than phosphate as occurs in normal DNA or RNA.
  • the PARP enzyme comprises four domains: a DNA-binding domain, a caspase-cleaved domain, an auto-modification domain, and a catalytic domain.
  • the DNA-binding domain comprises two zinc finger motifs. In the presence of damaged DNA, the DNA-binding domain will bind the DNA and induce a conformational shift. PARP can be inactivated by caspase-3 cleavage, which is a step that occurs in programmed cell death (apoptosis).
  • PARP1 and PARP2 are known, including PARP1 and PARP2. Of these two enzymes, PARP1 is responsible for most cellular PARP activity.
  • PARP1 The binding of PARP1 to single-strand breaks in DNA through the amino-terminal zinc finger motifs recruits XRCC1, DNA ligase III, DNA polymerase ⁇ , and a kinase to the nick. This is known as base excision repair (BER).
  • PARP2 has been shown to oligomerize with PARP1, and the oligomerization stimulates catalytic activity. PARP2 is also therefore implicated in BER.
  • PARP1 inhibitors inhibit the activity of PARP1 and thus inhibit the repair of single-strand breaks in DNA. When such breaks are unrepaired, subsequent DNA replication can induce double-strand breaks.
  • the proteins BRCA1, BRCA2, and PALB2 can repair double- strand breaks in DNA by the error-free homologous recombinational repair (HRR) pathway.
  • HRR homologous recombinational repair
  • normal cells do not replicate their DNA as frequently as tumor cells, and normal cells that lack mutated BRCA1 or BRCA2 proteins can PATENT EDISON-58717 still repair these double-strand breaks through homologous repair. Therefore, normal cells are less sensitive to the activity of PARP inhibitors than tumor cells.
  • Some tumor cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors because of downregulation of Rad51, a critical homologous recombination component.
  • PARP inhibitors are also considered potential treatments for other life-threatening diseases, including stroke and myocardial infarction, as well as for long-term neurodegenerative diseases (G. Graziani & C. Szabó, “Clinical Perspectives of PARP Inhibitors,” Pharmacol. Res. 52: 109-118 (2005)).
  • a number of PARP inhibitors are known in the art.
  • PARP inhibitors include, but are not limited to, iniparib, talazoparib, olaparib, rucaparib, veliparib, CEP- 9722 (a prodrug of CEP-8983 (11-methoxy-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)- dione), MK 4827 ((S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide), and BGB-290.
  • CEP- 9722 a prodrug of CEP-8983 (11-methoxy-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)- dione
  • MK 4827 ((S)-2-(4-(piperidin-3-yl)phenyl)-2H
  • United States Patent No. 9,062,043 to Chua et al. discloses fused tricyclic PARP inhibitors, including a compound of Formula (PA-II): (P-II).
  • United States Patent No. 9,018,201 to Chu et al discloses dihydropyridophthalazinone inhibitors of PARP.
  • United States Patent No. 8,993,594 to Papeo et al. discloses substituted isoquinolin-1(2H)-one derivatives as inhibitors of PARP.
  • PATENT EDISON-58717 United States Patent No. 8,980,902 to Brown et al. discloses substituted benzamide PARP inhibitors.
  • PARP inhibitors including: 2-methyl-6-((4-phenylpiperidin-1-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 2- methyl-6-((4-phenylpiperazin-1-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; and 6-((4-(4- fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)- one, as well as additional compounds. [0296] United States Patent No.
  • PARP inhibitors including: 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one; N-ethyl-4-(4-((6- oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; PATENT EDISON-58717 and N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3- yl)methyl)piperazin-1-yl)benzamide, as well as additional compounds.
  • United States Patent No. 8,541,403 to Chu et al. discloses dihydropyridophthalazinone derivatives as PARP inhibitors.
  • inhibitors of PARP including benzyl 2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)indoline-1-carboxylate; 2- (indolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide; tert-butyl 2-(4-carbamoyl-1H- benzo[d]imidazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate; and 2-(1,2,3,4- tetrahydroquinolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide, as well as additional compounds. [0302] United States Patent No.
  • tricyclic PARP inhibitors including: N-methyl[4-(6-oxo-3,4,5,6-tetrahydro-2H-azepino[5,4,3-cd]indazol-2- yl)phenyl]methanaminium trifluoroacetate; N,N-dimethyl[4-(6-oxo-3,4,5,6-tetrahydro-2H- azepino[5,4,3-cd]indazol-2-yl)phenyl]methanaminium trifluoroacetate; and N 2 ,N 2 -dimethyl-N- [4-(1-oxo-1,2,3,4-tetrahydroazepino[3,4,5-hi]indolizin-5-yl)phenyl]glycinamide, as well as additional compounds.
  • United States Patent No. 8,268,827 to Branca et al. discloses pyridazinone derivatives as PARP inhibitors, including: 6- ⁇ 4-fluoro-3-[(3-oxo-4-phenylpiperazin-1- yl)carbonyl]benzyl ⁇ -4,5-dimethyl-3-oxo-2,3-dihydropyridazin-1-ium trifluoroacetate; 6- ⁇ 3-[(4- PATENT EDISON-58717 cyclohexyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl ⁇ -4,5-dimethyl-3-oxo-2,3- dihydropyridazin-1-ium trifluoroacetate; 6- ⁇ 3-[(4-cyclopentyl-3-oxopiperazin-1-yl)carbonyl]-4- fluorobenzyl ⁇ -4,5-dimethylpyridazin-3(2H)-one; and
  • United States Patent No. 8,217,070 to Zhu et al. discloses 2-substituted-1H- benzimidazole-4-carboxamides as PARP inhibitors, including: 2-(1-aminocyclopropyl)-1H- benzimidazole-4-carboxamide; 2-[1-(isopropylamino)cyclopropyl]-1H-benzimidazole-4- carboxamide; 2-[1-(cyclobutylamino)cyclopropyl]-1H-benzimidazole-4-carboxamide; and 2- ⁇ 1- [(3,5-dimethylbenzyl)amino]cyclopropyl ⁇ -1H-benzimidazole-4-carboxamide, as well as additional compounds.
  • United States Patent No. 8,188,103 to Van der Aa et al. discloses substituted 2- alkyl quinazolinone derivatives as PARP inhibitors.
  • 2,3,5-substituted pyridone derivatives as PARP inhibitors including: 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro- pyridin-3-yl)-thiophene-2-sulfonic acid [3-(3-hydroxy-pyrrolidin-1-yl)-propyl]-amide hydrochloride; and 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonic acid [2-(1-methylpyrrolidin-2-yl)ethyl]amide hydrochloride, as well as additional compounds. [0310] United States Patent No.
  • PARP inhibitors of Formula (PA-III) PA-III
  • R1 is H, halogen, alkoxy, or lower alkyl
  • PATENT EDISON-58717 (2)
  • R2 is H, halogen, alkoxy, or lower alkyl
  • R3 is independently H, amino, hydroxy, --N--N, halogen-substituted amino, --O- alkyl, --O-aryl, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, --COR8, where R8 is H, --OH an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or --OR6 or --NR6R7 where R6 and R7 are each independently hydrogen or an optionally substituted alkyl, alkeny
  • United States Patent No. 8,088,760 to Chu et al. discloses benzoxazole carboxamide inhibitors of PARP, including: 2-(4- ((methylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide; 2-(2-methylpyrrolidin-2- yl)benzo[d]oxazole-4-carboxamide; 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7- carboxamide; 2-(2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide; and 2-(pyrrolidin-2- yl)benzo[d]oxazole-4-carboxamide, as well as additional compounds.
  • United States Patent No. 8,071,623 to Jones et al. discloses amide-substituted indazoles as PARP inhibitors, including: 2-(4-piperidin-3-ylphenyl)-2H-indazole-7-carboxamide; 2- ⁇ 4-[(3R)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide; 2- ⁇ 4-[(3S)-piperidin-3- yl]phenyl ⁇ -2H-indazole-7-carboxamide; 5-fluoro-2-(4-piperidin-3-ylphenyl)-2H-indazole-7- PATENT EDISON-58717 carboxamide; and 5-fluoro-2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, as well as additional compounds.
  • United States Patent No. 8,058,275 to Xu et al. discloses diazabenzo[de]anthracen-3-one compounds as PARP inhibitors.
  • United States Patent No. 8,012,976 to Wang et al. discloses dihydropyridophthalazinone compounds as PARP inhibitors, including 5-fluoro-8-(4- fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin- 3(7H)-one.
  • substituted aza-indole derivatives as PARP inhibitors including: 1-phenyl-2-(piperazin-1-yl)-1,3-dihydropyrrolo[2,3- b]pyridine-3-carboxaldehyde, 1-phenyl-2-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-3- carboxaldehyde, 2-[1,4]diazepan-1-yl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde trifluoroacetic acid salt, and 2-piperazin-1-yl-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3- carbaldehyde bis-trifluoroacetic acid salt, as well as additional compounds.
  • thieno[2,3- c]quinolones as PARP inhibitors, including compounds of Formula (PA-V): (PA-V), wherein: (1) Y is selected from sulfur, nitrogen, and oxygen; (2) R1, R2, R3, R4, R5 and R6 are the same or different, and each represent hydrogen, hydroxy, OR 7 , COOR 7 , carboxy, amino, NHR 7 or halogen, or R 5 and R 6 taken together form a fused non-aromatic 5- or 6-membered carbocylic ring; and (3) R7 is C1-C6 alkyl, C2-C6 alkenyl or C3-C7 cycloalkyl optionally substituted with one or more group selected from hydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 6 alkoxycarbonyl, amino, C 1 - C6 mono-alkylamino, C1-C6 di-alkylamino and halogen.
  • PA-V Formula (PA-V): (
  • United States Patent No. 7,820,668 to Xu et al. discloses diazabenzo[de]anthracen-3-one compounds as PARP inhibitors.
  • United States Patent No. 7,732,491 to Sherman et al. discloses 4-iodo-3- nitrobenzamide as a PARP inhibitor.
  • United States Patent No. 7,550,603 to Zhu et al. discloses 1H-benzimidazole-4- carboxamides substituted with a quaternary carbon at the 2-position as PARP inhibitors, including 2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide; 2-[(2R)-2- methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide; 2-[(2S)-2-methylpyrrolidin-2-yl]-1H- benzimidazole-4-carboxamide; 2-(1,2-dimethylpyrrolidin-2-yl)-1H-benzimidazole-4- carboxamide; 2-(1-ethyl-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide; and 2-(2- methyl-1-propylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, as well as additional
  • United States Patent No. 7,087,637 to Grandel et al. discloses indole derivatives as PARP inhibitors, including: 2-(4(4-n-propyl-piperazin-1-yl)-phenyl)-1H-indol-4-carboxamide; 2-(4-piperazin-1-yl-phenyl)-1H-indol-4-carboxamide; 2-(4(4-isopropyl-piperazin-1-yl)-phenyl)- 1H-indol-4-carboxamide; 2-(4(4-benzyl-piperazin-1-yl)-phenyl)-1H-indol-4-carboxamide; 2- (4(4-n-butyl-piperazin-1-yl)-phenyl)-1H-indol-4-carboxamide; and 2-(4(4-ethyl-piperazin-1-yl)- phenyl)-1H-indol-4-carboxamide
  • United States Patent No. 6,635,642 to Jackson et al. discloses phthalazinone derivatives as PARP inhibitors, including 4-(3-nitro-4-(piperidin-1-yl)phenyl-phthalazin-1(2H)- one; 4-(4-(dimethylamino)-3-nitrophenyl)-phthalazin-1(2H)-one; 4-(3-amino-4- (dimethylamino)phenyl)-phthalazin-1(2H)-one; 4-(4-phenylpiperazin-1-yl)-phthalazin-1(2H)- one; and 4-(4-(4-chlorophenyl)-piperazin-1-yl)-phthalazin-1(2H)-one, as well as additional compounds.
  • United States Patent No. 6,448,271 to Lubisch et al. discloses substituted benzimidazoles as PARP inhibitors, including 2-(piperidin-4-yl)benzimidazole-4-carboxamide dihydrochloride; 2-(N-acetylpiperidin-4-yl)benzimidazole-4-carboxamide; 2-(N-propylpiperidin- 4-yl)benzimidazole-4-carboxamide; 2-piperidin-3-ylbenzimidazole-4-carboxamide dihydrochloride; and 2-(N-(O-t-butoxycarbonyl)piperidin-3-yl)benzimidazole-4-carboxamide; 2- (N-benzylpiperidin-3-yl)benzimidazole-4-carboxamide, as well as additional compounds.
  • United States Patent No. 6,426,415 to Jackson et al. discloses alkoxy-substituted PARP inhibitors, including 1-(benzyloxy)-5-methylphthalazine; 1-(methoxy)-5-methyl- phthalazine; 1-(ethoxy)-5-methylphthalazine; 1-(propoxy)-5-methylphthalazine; 1-(butoxy)-5- methyl-phthalazine; 1-(methoxy)-5-hydroxyphthalazine; 1-(ethoxy)-5-hydroxyphthalazine; 1- (propoxyoxy)-5-hydroxy-phthalazine; and 1-(butoxy)-5-hydroxyphthalazine, as well as additional compounds.
  • United States Patent No. 6,426,415 to Jackson et al. discloses alkoxy-substituted PARP inhibitors, including 1-(benzyloxy)-5-methylphthalazine; 1-(methoxy)-5-methyl- phthalazine; 1-(ethoxy)-5-methylphthalazine; 1-(prop
  • United States Patent No. 6,380,211 to Jackson et al. discloses alkoxy-substituted PARP inhibitors, including 1-(methoxy)-5-methylisoquinoline, 1-(ethoxy)-5-methyl- isoquinoline, 1-(propoxy)-5-methylisoquinoline, 1-(butoxy)-5-methylisoquinoline, 1-(ethoxy)-5- hydroxy-isoquinoline, 1-(propoxy)-5-hydroxyisoquinoline, 1-(butoxy)-5-hydroxyisoquinoline, 1- PATENT EDISON-58717 (benzyloxy)-5-methylphthalazine and 1-(benzyloxy)-5-methylisoquinoline, as well as additional compounds. [0335] United States Patent No.
  • United States Patent No. 5,756,510 to Griffin et al. discloses benzamide analogs that are PARP inhibitors, including: 3-benzyloxybenzamide; 3-(4-methoxybenzyloxy)benzamide; 3-(4-nitrobenzyloxy)benzamide; 3-(4-azidobenzyloxy)benzamide; 3-(4- bromobenzyloxy)benzamide; 3-(4-fluorobenzyloxy)benzamide; 3-(4- PATENT EDISON-58717 aminobenzyloxy)benzamide; 3-(3-nitrobenzyloxy)benzamide; 3-(3,4- methylenedioxyphenylmethyloxy)benzamide; 3-(piperonyloxy)benzamide; 3-(N-acetyl-4- aminobenzyloxy)benzamide; and 3-(4-trifluoromethylbenzyloxy)benzamide; and 3-(4- cyanobenzyloxy)benzamide, as well as additional compounds.
  • United States Patent Application Publication No. 2015/0152118 by Jana et al. discloses tetrahydroquinazolinone derivatives as PARP inhibitors, including: 2′-(3-(4-(4- fluorophenyl)piperazin-1-yl)propyl)-6′,7′-dihydro-3′H-spiro[cyclopropane-1,8′-quinazolin]- 4′(5′H)-one; 2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-6',7'-dihydro-3′H- spiro[cyclopropane-1,8′-quinazolin]-4′(5′H)-one; 2′-(3-(4-phenyl-5,6-dihydropyridin-1(2H)- yl)propyl)-6′,7′-dihydro-3′H-spiro
  • United States Patent Application Publication No. 2015/0018356 by Zhou et al. discloses fused tetra- or pentacyclic pyridophthalazinones as PARP inhibitors.
  • elesclomol can potentiate the activity of PARP inhibitors, inhibitors of histone deacetylase, and hypomethylating agents; inhibitors of histone deacetylase and hypomethylating agents are epigenetic targets.
  • Histone deacetylase inhibitors include, but are not limited to, parthenolide, abexinostat, allyl mercaptan, apicidin, belinostat, chidamide, 3,3′-diindolylmethane, entinostat, givinostat, martinostat, mocetinostat, panobinostat, pracinostat, resminostat, romidepsin, trichostatin A, and vorinostat.
  • Hypomethylating agents include, but are not limited to, azacitidine and decitabine.
  • Other inhibitors of the A form of lactate dehydrogenase are described in E.-Y.
  • Inhibitors of the A form of lactate dehydrogenase disclosed in this reference include: 1- (phenylseleno)-4-bromobenzene, 1-(phenylseleno)-4-methylbenzene, 1-(phenylseleno)-4- methoxybenzene, 1-(phenylseleno)-4-phenylbenzene, 3-(phenylseleno)tetrahydrothiophene, and 1-(phenylmethylseleno-4-methoxybenzene.
  • Glutamine metabolism inhibitors include compound 968 (5-(3-bromo-4- (dimethylamino)phenyl)-2,2-dimethyl-2,3,5,6-tetrahydrobenzo[a]phenanthridin-4(1H)-one), BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazoyl-2-yl)ethyl sulfide), L-asparaginase, and phenylbutyrate.
  • Other glutamine metabolism inhibitors are disclosed in United States Patent No.
  • inhibitors of glutamine synthase such as methionine sulfoximine, methionine sulfone, phosphinothricin, tabtoxinin- ⁇ -lactam, methionine sulfoximine phosphate, ⁇ -methyl methionine sulfoximine, ⁇ -ethyl methionine sulfoximine, ethionine sulfoximine, ⁇ -methyl ethionine sulfoximine, prothionine sulfoximine, ⁇ -methyl prothionine sulfoximine, ⁇ -hydroxy phosphinothricin, gamma-methyl phosphinothricin, ⁇ - acetoxy phosphinothricin, ⁇ -methyl phosphinothricin, ⁇ -ethyl phosphinothricin, cyclohex
  • GS glutamine synthase
  • G-I PATENT EDISON-58717
  • X is selected from the group consisting of a bond, --O--, and –(CH2) n --, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8
  • R1 is selected from the group consisting of hydrogen and a first prodrug-forming moiety capable of forming a salt or an ester
  • R2 is selected from the group consisting of hydrogen and a second prodrug-forming moiety capable of forming an amide linkage, a carbamate linkage, a phosphoramidate linkage or a phosphorodiamidate linkage with the nitrogen adjacent to R 2
  • R2′ is
  • R1 is phenyl optionally substituted with at least one R3, benzyl optionally substituted with at least one R 3 , or pyridinyl optionally substituted with at least one R 3 ;
  • R2 is phenyl optionally substituted with at least one R3, benzyl optionally substituted with at least one R3, or pyridinyl optionally substituted with at least one R3;
  • R 3 is independently hydrogen, methyl, alkyl, methoxy, alkoxy, halogen, or trifluoromethyl; and (4) n is 0-6.
  • DNA-damaging agents include (S)-2-amino-4-(bis(2-((3- methylbenzyl)oxy)benzyl)amino)butanoic acid.
  • Other inhibitors of glutamine metabolism are known in the art.
  • a sixth category of suitable additional agents is DNA-damaging agents, in particular, DNA-damaging anti-neoplastic agents.
  • DNA-damaging anti-neoplastic agents are disclosed in K. Cheung-Ong et al., “DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology,” Chem. Biol. 20: 648-659 (2013). These agents fall into several categories.
  • agents that damage DNA directly are agents that employ one of several mechanisms, including direct modification of DNA bases, intercalation between DNA bases, and formation of crosslinks in DNA.
  • Another category is agents that interfere with DNA synthesis.
  • agents that inhibit topoisomerases are agents that inhibit topoisomerases; some of these agents also have additional activities that can damage DNA or interfere with DNA replication in various other ways.
  • PATENT EDISON-58717 [0367] For example, nitrogen mustards act by directly alkylating DNA on purine bases, leading to stalled replication fork progression and subsequent cell death via apoptosis.
  • DNA alkylators cyclophosphamide, chlorambucil, and melphalan, all of which are currently used in clinical therapeutics.
  • DNA-alkylating agents used in cancer treatment include nitrosoureas (e.g., carmustine, lomustine, and semustine) and triazenes (e.g., dacarbazine and temozolomide).
  • Natural products which alkylate DNA bases were also discovered, such as mitomycin C and streptozotocin.
  • interstrand cross-links crosslink DNA on opposite strands of the double helix (interstrand cross-links), resulting in a more potent effect against cancer cells compared to monofunctional alkylation.
  • carmustine binds to the N1 atom of guanine on one DNA strand and the N3 atom of cytosine of the opposite strand to form interstrand crosslinks, which block DNA replication and can cause cell death if not repaired.
  • Additional agents that damage DNA include the alkylating-like platinum agents that act by forming adducts on DNA. When two platinum adducts form on adjacent bases on the same DNA strand, they form intrastrand crosslinks.
  • Antimetabolites typically do not damage DNA molecules directly, but interfere with DNA replication. Examples include the pyrimidine analogs 5-fluorouracil, capecitabine, floxuridine, and gemcitabine, and the purine analogs 6-mercaptopurine, 8-azaguanine, fludarabine, and cladribine.
  • Another class of antimetabolites inhibit enzymes important for DNA synthesis; this class of antimetabolites include antifolates such as methotrexate, aminopterin, pemetrexed, and ralitrexed.
  • DNA-damaging anti-neoplastic agents can act by a variety of mechanisms, including modification of DNA bases such as by alkylation, intercalation into the DNA structure, formation of crosslinks in DNA, prevention of unwinding or replication of DNA to induce double-strand breaks, incorporation into DNA in place of normal nucleosides, and other mechanisms.
  • DNA-damaging anti-neoplastic agents include, but are not limited to: cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin, satraplatin, tetraplatin, doxorubicin, daunorubicin, methotrexate, 5-fluorouracil, gemcitabine, podophyllotoxin, etoposide, teniposide, cyclophosphamide, chlorambucil, melphalan, carmustine, lomustine, estramustine, semustine, bendamustine, prednamustine, uramustine, chlornaphazine, dacarbazine, altretamine, temozolomide, mitomycin C, streptozotocin, chlorozotocin, capecitabine, floxuridine, 6- mercaptopurine, 8-azaguanine, azathiopurine, 5-ethynyluracil, thio
  • SWI/SNF a seventh category of suitable additional agents is agents that inhibit the SWI/SNF complex.
  • the SWI/SNF (BAF) complexes are a diverse family of ATP-dependent PATENT EDISON-58717 chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases.
  • SWI/SNF inhibitors are compounds that inhibit one or more members of a subfamily of ATP-dependent chromatin remodeling complexes; the activity of these proteins affects nucleosome rearrangement, which, in turn, affects access to the chromatin, allowing genes to be activated or repressed.
  • SWI/SNF inhibitors include BD98 (1-isopropyl-3-((4R,5S,8S)-4-methoxy-2,5,8- trimethyl-1-oxo-7-(4-pyridyl-2-yl)benzyl)-1,2,3,4,5,6,7,8,9,10- decahydrobenzo[h][1,6]diazacyclododecin-13-yl)urea) (E.J. Chory et al., “Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing,” ACS Chem. Biol. 15: 1685-1696 (2020)).
  • the ATR inhibitor described in this reference is 3-amino-6- (4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide.
  • SWI/SNF inhibitors are disclosed in United States Patent Application Publication No. 2020/0147120 by Iba et al. and United States Patent No. 9,850,543 to Zainab et al.
  • An eighth category of additional agents is agents that cause the tumor cells to rely heavily on oxidative phosphorylation (OXPHOS). It had been previously shown that cancer cells exhibit an alteration in their metabolism when compared with non-malignant cells.
  • the enzymes that catalyze reactions in the glycolytic pathway include: hexokinase; glucose-6-phosphate isomerase; phosphofructokinase 1; fructose-bisphosphate aldolase; triosephosphate isomerase; glyceraldehyde 3-phosphate dehydrogenase; phosphoglycerate kinase; phosphoglycerate mutase; enolase; and pyruvate kinase.
  • extracellular glucose is transported into the cell by the glucose transporter GLUT1, and the activity of this glucose transporter may also be a potential PATENT EDISON-58717 therapeutic target.
  • Inhibitors of hexokinase include 3-bromopyruvate.
  • Inhibitors of phosphofructokinase 1 include 3-(3-pyridinyl)-1-(4-pyridinyl)-2- propen-1-one and PFK158 (1-(4-pyridinyl)-3-[7-(trifluoromethyl)-2E-quinolinyl]-2-propen-1- one.
  • Other inhibitors of glycolysis do not directly inhibit the enzymes that are part of the glycolysis pathway itself but can interfere with glycolysis by other routes.
  • NHI-1 (1-hydroxy-6-phenyl-4-trifluoromethyl- 1H-indole-2-carboxylic acid
  • NHI-2 methyl 1-hydroxy-6-phenyl-4-trifluoromethyl-1H- indole-2-carboxylate
  • lactate dehydrogenase inhibitors by diminishing lactate production, these compounds stimulate oxidative phosphorylation and inhibit glycolysis by feedback inhibition.
  • G-III PATENT EDISON-58717
  • X is selected from the group consisting of nitro, an imidazole, a halide, sulfonate, a carboxylate, an alkoxide, and amine oxide
  • R is selected from the group consisting of OR′, N(R′′)2, C(O)R′′′, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, hydrogen, and an alkali metal
  • R′ is hydrogen, an alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R′′′
  • R′′ is hydrogen, C1-C6 alkyl, or C6-C12 aryl
  • R′′′ is hydrogen, C1-C20 alkyl, or
  • United States Patent No. 8,927,506 to Priebe et al. discloses acetates of 2- deoxymonosaccharides as inhibitors of glycolysis.
  • United States Patent No. 8,329,753 to Newell et al. discloses bifunctional compounds that covalently link a glycolysis inhibitor and a fatty acid metabolism inhibitor.
  • the anti-neoplastic agent lonidamine can be used together with elesclomol or a derivative or analog of elesclomol; in this context, lonidamine acts as an additional agent that causes the tumor cells to rely heavily on oxidative phosphorylation.
  • Lonidamine is an agent that suppresses glycolysis in tumor cells through the inhibition of the mitochondrially bound hexokinase.
  • Another agent that acts as an additional agent that causes the tumor cells to rely heavily on oxidative phosphorylation is the alkylating agent dianhydrogalactitol. Dianhydrogalactitol is described in PCT Patent Application Publication No. WO 2012/024367 by Brown.
  • a ninth category of additional agents is agents that act as inhibitors of the base excision repair (BER) pathway. PATENT EDISON-58717 [0391] Inhibitors of the base excision repair (BER) pathway as anti-neoplastic agents are disclosed in A.M.
  • inhibitors include: (i) PARP inhibitors, specifically INO-1001 (3-aminobenzamide); AG14361 (2-[4-[(dimethylamino)methyl]phenyl]-1,3,10- triazatricyclo[6.4.1.04,13]trideca-2,4,6,8(13)-tetraen-9-one); AG014699 (rucaparib phosphate); ABT-888 (veliparib); and AZD2281 (olaparib); (ii) inhibitors of the Ape1 enzyme, including methoxyamine; lucanthone; 7-nitroindole-2-carboxylic acid; an arylstilbonic acid derivative (A.
  • INO-1001 3-aminobenzamide
  • AG14361 (2-[4-[(dimethylamino)methyl]phenyl]-1,3,10- triazatricyclo[6.4.1.04,13]trideca-2,4,6,8(13)-tetraen-9-one
  • AG014699 rucapa
  • the AP endonuclease inhibitor can be methoxyamine, the compound of Formula (B-I), or N-ethylmaleimide.
  • the PARP inhibitor can be 5-methyl-3,4-dihydro-2H-isoquinolin-1- one (PD128763), 3-aminobenzamide, 6-aminonicotinamide, 8-hydroxy-2-methyl-3H-quinazolin- 4-one (NU1025), or 4-amino-1,8-naphthalimide.
  • the DNA polymerase inhibitor can be prunasin, aphidicolin, ddCTP, ddTTP, ddATP, ddGTP, or arabinocytidine.
  • HR homologous repair
  • agents include imatinib mesylate, erlotinib, valproic acid, abexinostat, tanespimycin, ⁇ -lactacystin, benzyl N-[(2S)-4-methyl-1- [[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1- oxopentan-2-yl]carbamate (MG-132), bortezomib, nelfinavir, mirin, 6-(cyclohexylmethoxy)-5- nitrosopyrimidine-2,4-diamine (NU6027), 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)- piperidin-3-yl]thiophene-2-carboxamide (AZD7762), (5Z)-5-(quinolin-6
  • United States Patent No. 10,927,075 to Mills discloses inhibitors of homologous repair including 4,4′-diisothiocyanatostilbene-2,2′-disulfonate.
  • United States Patent No. 10,590,122 to Castro et al. discloses substituted thiazole derivatives as RAD51 inhibitors that function as inhibitors of homologous repair; the substituted thiazole derivatives can include a cycloalkyl, heterocyclyl, or heteroaromatic moiety.
  • PATENT EDISON-58717 An eleventh category of additional agents is antineoplastic agents that can activate homologous repair as part of their mechanism of antineoplastic activity or as a consequence of inducing DNA damage.
  • additional agents include carboplatin, cisplatin, dianhydrogalactitol, and dibromodulcitol.
  • additional agents include carboplatin, cisplatin, dianhydrogalactitol, and dibromodulcitol.
  • a twelfth category of additional agents is antineoplastic agents that are activated by bioreductases under acute conditions of hypoxia or that function to sensitize hypoxic cells to antineoplastic agents or radiation. These agents include hypoxic cell sensitizers and cytotoxic agents.
  • Hypoxic cell sensitizers include, but are not necessarily limited to, misonidazole, metronidazole, nimorazole, benznidazole, desmethylmisonidazole, etanidazole, pimonidazole, and 1-(aziridin-1-yl)-3-(2-nitroimidazol-1-yl)propan-2-ol (RSU-1069) (S. Dische, “Chemical Sensitizers for Hypoxic Cells: A Decade of Experience in Clinical Radiotherapy,” Radiother. Oncol. 3: 97-115 (1985)). Cytotoxic agents that can be activated by bioreductases include, but are not limited to, tirapazamine and mitomycin C.
  • Tirapazamine produces hydroxyl and/or benzotriazinyl radicals as DNA-damaging reactive species.
  • Mitomycin C is an alkylating agent that crosslinks DNA; it is reductively activated to form a mitosene, which reacts successively via N-alkylation of two DNA bases. Both alkylations are sequence-specific for a guanine nucleoside in the sequence 5′-CpG-3′.
  • a thirteenth category of additional agents is agents that inhibit cysteine uptake.
  • One class of agents that inhibits cysteine uptake is peptides derived from digestion of human ⁇ -casein, bovine ⁇ -casein, and gliadin.
  • peptides include human ⁇ - casomorphin-7 (hBCM7) (YPFVEPL) (SEQ ID NO: 1); bovine ⁇ -casomorphin-7 (bBCM7) (YPFPGPL) (SEQ ID NO: 2); and gliadinomorphin-7 (GM7) (YPQPQPF) (SEQ ID NO: 3) (M.S. Trivedi, “Food-Derived Opioid Peptides Inhibit Cysteine Uptake with Redox and Epigenetic Consequences,” J. Nutr. Biochem. 25: 1011-1018 (2014)).
  • Another class of agents that inhibits cysteine uptake is inhibitors of the excitatory amino acid transporters (EAATs) EAAT2 and EAAT3. These inhibitors include L-glutamate, L- aspartate, and the synthetic inhibitors threo- ⁇ -hydroxyaspartate, which is a non-selective EAAT inhibitor, and dihydrokainate, which is a selective EAAT2 inhibitor.
  • Another cysteine uptake inhibitor is threo- ⁇ -benzyloxyaspartate (Y. Chen & R.A. Swanson, “The Glutamate Transporters EAAT2 and EAAT3 Mediate Cysteine Uptake in Cortical Neuron Cultures,” J. Neurochem.
  • R 1 is selected from the group consisting of hydrogen, --Z-Q-Z--, --(C1-C8)alkyl- N(R 2 )(R 4 ), --(C 1 -C 8 )alkyl-OR 3 , 3- to 8-membered carbocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, and (C1-C4) aralkyl;
  • R 2 and R 4 are each independently selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R 2 and R 4 are on the same nitrogen atom and not both hydrogen they are different and that when both R 2 and R 4 are on
  • erastin analogs include piperazine erastin (2-[[4-[2-(4- chlorophenoxy)acetyl]piperazin-1-yl]methyl]-3-[5-(piperazin-1-ylmethyl)-2-propan-2- yloxyphenyl]quinazolin-4-one) (United States Patent No. 9,695,133 to Stockwell et al.). [0407] United States Patent Application Publication No. 2007/0161644 by Stockwell discloses erastin analogs.
  • R 1 is selected from the group consisting of hydrogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy, 3- to 8-membered carbocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, residues of glycolic acid, residues of ethylene glycol/propylene glycol copolymers, carboxylate, ester, amide, carbohydrate, amino acid, alditol, OC(R 7 ) 2 COOH, SC(R 7 ) 2 COOH, NHCHR 7 COOH, COR 8 , CO2R 8 , sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, and thioether; (2) R 2 , R 3 ,
  • Yet another class of inhibitors of cysteine uptake includes inhibitors of other transporters of cysteine, or, in some cases, its oxidized form cystine.
  • additional transporters include LAT1, ASCT2, and the X c - system (B. Daher et al., “Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptic Cell Death,” Front. Oncol. 10:723 (2020)).
  • LAT1 is responsible for transport of essential amino acids, general amino acid homeostasis, and, consequently tumor growth.
  • ASCT2 is a transporter that exchanges small neutral amino acids and plays a crucial role in glutamine uptake and the promotion of tumor growth, independently of LAT1 activity; however, there is evidence that this transporter may not actually be involved in the transport of cysteine in vivo and that cysteine may actually be a competitive inhibitor of ASCT2.
  • the third transporter of relevance is the Xc- system, which is an exchanger that imports cystine (the oxidized form of cysteine) and exports glutamate.
  • This sodium-independent antiporter comprises two subunits: xCT (encoded by the gene SLC7A11), a subunit responsible for the amino acid exchange, and a chaperone CD98 (encoded by the gene SLC3A2).
  • Inhibitors of the Xc- system include erastin, imidazole ketone erastin (IKE), sorafenib, and sulfasalazine (SSZ).
  • IKE imidazole ketone erastin
  • SSZ sulfasalazine
  • GCN2 General Control Nonderepressible
  • one aspect of the present invention is a method to improve the efficacy and/or reduce the side effects of the administration of elesclomol or a derivative, analog, salt, or solvate of elesclomol for treatment of a malignancy, particularly OCCC, more particularly OCCC that has progressed beyond FIGO stage 1 or that has metastasized, or, alternatively, OCCC occurring in a patient with a loss-of-function mutation in ARID1A, the method comprising the steps of: (1) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the administration of the elesclomol or a derivative, analog, salt, or solvate of elesclomol for the treatment of the malignancy; and (2) modifying the factor or parameter to improve the efficacy
  • the factor or parameter is selected from the group consisting of: (1) dose modification; (2) route of administration; (3) schedule of administration; (4) patient selection; (5) patient/disease phenotype; (6) patient/disease genotype; (7) pre/post-treatment preparation; (8) toxicity management; (9) pharmacokinetic/pharmacodynamic monitoring; (10) drug combinations; (11) chemosensitization; PATENT EDISON-58717 (12) chemopotentiation; (13) post-treatment patient management; (14) bulk drug product improvements; (15) diluent systems; (16) solvent systems; (17) excipients; (18) dosage forms; (19) dosage kits and packaging; (20) drug delivery systems; (21) drug conjugate forms; (22) compound analogs; (23) prodrug systems; (24) multiple drug systems; (25) biotherapeutic enhancement; (26) biotherapeutic resistance modulation; (27) radiation therapy enhancement; (28) novel mechanisms of action; (29) selective target cell population therapeutics; (30) reversal of resistance to an agent selected from the group
  • the schedule of administration can be, but is not limited to, a schedule of administration selected from the group consisting of: PATENT EDISON-58717 (a) daily administration; (b) weekly administration for three weeks; (c) weekly administration for two weeks; (d) biweekly administration; (e) biweekly administration for three weeks with a 1-2 week rest period; (f) intermittent boost dose administration; (g) daily administration for one week then administration once per week for multiple weeks; (h) daily administration on days 1-5, 8-12 every three weeks; and (i) daily administration on days 1-3, 8-11 per cycle.
  • a schedule of administration selected from the group consisting of: PATENT EDISON-58717
  • the patient selection can be, but is not limited to, a method of patient selection selected from the group consisting of: (a) selecting patients with disease conditions with high levels of metabolic enzymes; (b) selecting patients with disease conditions with high levels of reactive oxygen species; (c) selecting patients with disease conditions with high levels of histone deacetylase; (d) selecting patients with disease conditions with high levels of protein kinases; (e) selecting patients with disease conditions with high levels of ornithine decarboxylase; (f) selecting patients with disease conditions with low levels of metabolic enzymes; (g) selecting patients with disease conditions with low levels of reactive oxygen species; (h) selecting patients with disease conditions with low levels of histone deacetylase; PATENT EDISON-58717 (i) selecting patients with disease conditions with low levels of protein kinases; (j) selecting patients with disease conditions with low levels of ornithine decarboxylase; (k) selecting patients with low or high susceptibility to thrombocytopenia
  • the analysis of patient or disease phenotype can be, but is not limited to, an analysis of patient or disease phenotype selected from the group consisting of: (a) use of diagnostic tools, techniques, kits and assays to confirm a patient’s particular phenotype; (b) measurement of metabolism enzymes and metabolites; (c) measurement of histone deacetylase; (d) measurement of protein kinases; (e) measurement of ornithine decarboxylase; (f) measurement of VEGF; PATENT EDISON-58717 (g) measurement of products of prostate specific genes; (h) measurement of protein kinases; (i) measurement of telomerase; (j) measurement of jun; (k) measurement of GPCR’s; (l) use of surrogate compound dosing; (m) low dose drug pre-testing for enzymatic status; and (n) determination of ARID1A phenotypic status
  • GPCR receptors include, but are not limited to, acetylcholine receptors, ⁇ -adrenergic receptors, ⁇ 3 -adrenergic receptors, serotonin (5-hydroxytryptamine) receptors, dopamine receptors, adenosine receptors, angiotensin Type II receptors, bradykinin receptors, calcitonin receptors, calcitonin gene-related receptors, cannabinoid receptors, cholecystokinin receptors, chemokine receptors, cytokine receptors, gastrin receptors, endothelin receptors, ⁇ -aminobutyric acid (GABA) receptors, galanin receptors, glucagon receptors, glutamate receptors, luteinizing hormone receptors, choriogonadotrophin receptors, follicle-stimulating hormone receptors, thyroid-stimulating PATENT EDISON-58717 hormone receptors, gonadotrophin-releasing hormone receptor
  • Leucovorin is a reduced form of folic acid that bypasses dihydrofolate reductase and restores hematopoietic function. Leucovorin can be administered either intravenously or orally. [0425] In one alternative, wherein the pre/post treatment is the use of a uricosuric, the uricosuric is probenecid or an analog thereof.
  • Filgrastim is a granulocytic colony-stimulating factor (G-CSF) analog produced by recombinant DNA technology that is used to stimulate the proliferation and differentiation of granulocytes and is used to treat neutropenia; G-CSF can be used in a similar manner.
  • G-CSF is granulocyte macrophage colony-stimulating factor and stimulates stem cells to produce granulocytes (eosinophils, neutrophils, and basophils) and monocytes; its administration is useful to prevent or treat infection.
  • Anti-inflammatory agents are well known in the art and include corticosteroids and non-steroidal anti-inflammatory agents (NSAIDs).
  • Corticosteroids with anti-inflammatory activity include, but are not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide, and fludrocortisone.
  • the pharmacokinetic/pharmacodynamic monitoring can be, but is not limited to, a method selected from the group consisting of: (a) multiple determinations of drug plasma levels; (b) multiple determinations of metabolites in the blood or urine; (c) measurement of polyamines; (d) measurement of LAT-1 surface receptors; (e) use of gene sequencing; and PATENT EDISON-58717 (f) measurement of immune effectors.
  • determination of blood plasma levels or determination of at least one metabolite in blood or urine is carried out by immunoassays.
  • the drug combination can be, but is not limited to, a drug combination selected from the group consisting of: (a) use with topoisomerase inhibitors; (b) use with fraudulent nucleosides; (c) use with fraudulent nucleotides; (d) use with thymidylate synthetase inhibitors; (e) use with signal transduction inhibitors; (f) use with cisplatin or gallium analogs; (g) use with nitrosourea alkylating agents (BCNU, Gliadel wafers, CCNU); (h) use with bendamustine (Treanda); (i) use with anti-tubulin agents; (j) use with antimetabolites; (k) use with berberine; (l) use with apigenin; (m) use with amonafide; (n) colchicine or an analog thereof; (o) use with genistein; (p) use with etoposide; (q)
  • Bendamustine is a chemotherapeutic alkylating agent for the treatment of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphoma and can be administered in combination with etoposide, fludarabine, mitoxantrone, methotrexate, prednisone, rituximab, vincristine, and 90 Y-ibritumomab tiuxetan.
  • Alkylating agents can include nitroso-containing alkylating agents.
  • Berberine has antibiotic activity and prevents and suppresses the expression of pro-inflammatory cytokines and E-selectin, as well as increasing adiponectin expression.
  • Apigenin is a flavone that can reverse the adverse effects of cyclosporine and has chemoprotective activity, either alone or derivatized with a sugar.
  • Colchicine is a tricyclic alkaloid that exerts its activity by binding to the protein tubulin.
  • Analogs of colchicine include, but are not limited to, colchiceinamide, N- desacetylthiocolchicine, demecolcine, N-acetyliodocolchinol, trimethylcolchicinic acid (TMCA) methyl ether, N-acetylcolchinol, TMCA ethyl ether, isocolchicine, isocolchiceinamide, iso- TMCA methyl ether, colchiceine, TMCA, N-benzoyl TMCA, colchicosamide, colchicoside, colchinol and colchinoic acid (M.H. Zweig & C.F.
  • Genistein is an isoflavone with the systemic name 5,7-dihydroxy-3-(4- hydroxyphenyl)chromen-4-one.
  • Erbitux is a chimeric monoclonal antibody that inhibits epidermal growth factor receptor (EGFR) and is used to treat squamous cell carcinoma of the head and neck.
  • PD-1 inhibitors include pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, MGA012, AMP-224, and AMP-514.
  • PD-L1 inhibitors include atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA-170, and BMS-986189.
  • PL-1 and PDL-1 inhibitors are checkpoint inhibitors and can be used to treat malignancies by preventing the malignancy from evading the immune system.
  • Prednimustine is an alkylating agent that is an ester formed from prednisolone and chlorambucil and is used in the treatment of leukemias and lymphomas.
  • the chemosensitization can be, but is not limited to, use as chemosensitizer with an additional agent selected from the group consisting of: (a) fraudulent nucleosides; (b) fraudulent nucleotides; (c) thymidylate synthetase inhibitors; (d) signal transduction inhibitors; (e) cisplatin or gallium analogs; (f) an alkylating agent such as BCNU, Gliadel wafers, CCNU, bendamustine (Treanda), or temozolomide (Temodar); PATENT EDISON-58717 (g) anti-tubulin agents; (h) antimetabolites; (i) berberine; (j) apigenin; (k) amonafide; (l) colchicine and analogs; (m) genistein; (n) etop
  • an additional agent selected from the group consisting of: (a) fraudulent nucleosides; (b) fraudulent nucleotides
  • the diluent system can be, but is not limited to, a diluent system selected from the group consisting of: (a) an emulsion; (b) DMSO; (c) NMF; (d) DMF; PATENT EDISON-58717 (e) DMA; (f) ethanol; (g) benzyl alcohol; (h) dextrose-containing water for injection; (i) Cremophor; (j) cyclodextrins; (k) PEG; (l) a sweetening agent such as saccharin; (m) glycerol; and (n) a taste masking effector such as menthol, rum flavor, or fruit flavorings.
  • a diluent system selected from the group consisting of: (a) an emulsion; (b) DMSO; (c) NMF; (d) DMF; PATENT EDISON-58717 (e) DMA; (f) ethanol; (g) benzyl
  • the excipient can be, but is not limited to, an excipient selected from the group consisting of: (a) mannitol; (b) albumin; (c) EDTA; (d) sodium bisulfite; PATENT EDISON-58717 (e) benzyl alcohol; (f) carbonate buffers; (g) phosphate buffers; (h) glycerin; (i) sweeteners; (j) a taste masking agent; (k) substituted celluloses; and (l) sodium azide as a preservative.
  • an excipient selected from the group consisting of: (a) mannitol; (b) albumin; (c) EDTA; (d) sodium bisulfite; PATENT EDISON-58717 (e) benzyl alcohol; (f) carbonate buffers; (g) phosphate buffers; (h) glycerin; (i) sweeteners; (j) a taste masking agent; (k) substituted celluloses
  • the excipient can be, but is not limited to, a dosage form selected from the group consisting of: (a) tablets; (b) capsules; (c) topical gels; (d) topical creams; (e) patches; (f) suppositories; (g) lyophilized dosage fills, (h) suppositories with quick release of ⁇ 15 min or long melt times of >15 min release time; and (i) temperature adjusted suppositories.
  • a dosage form selected from the group consisting of: (a) tablets; (b) capsules; (c) topical gels; (d) topical creams; (e) patches; (f) suppositories; (g) lyophilized dosage fills, (h) suppositories with quick release of ⁇ 15 min or long melt times of >15 min release time; and (i) temperature adjusted suppositories.
  • Vacuum is then turned on, the shelf temperature is adjusted to -5° C, and primary drying is performed for 8 hours; the shelf temperature is again adjusted to -5° C and drying is carried out for at least 5 hours.
  • Secondary drying is started after the condenser (set at -60° C) and vacuum are turned on. In secondary drying, the shelf temperature is controlled at +5° C for 1 to 3 hours, typically 1.5 hours, then at 25°C for 1 to 3 hours, typically 1.5 hours, and finally at 35-40° C for at least 5 hours, typically for 9 hours, or until the product is completely dried.
  • Break the vacuum with filtered inert gas e.g., nitrogen). Stopper the vials in the lyophilizer.
  • the dosage kits and packaging can be, but are not limited to, a dosage kit or packaging selected from the group consisting of: (a) amber vials to protect from light; (b) stoppers with specialized coatings to improve shelf-life stability; (c) special dropper measuring devices; (d) single-use or multiple-use container closure systems; PATENT EDISON-58717 (e) suppository delivery devices; and (f) dosage measuring devices.
  • Bioerodible polymers also known as biodegradable polymers, are disclosed in N. Kamaly et al., “Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release,” Chem. Rev. 116: 2602-2663 (2016). Bioerodible polymers are also described in United States Patent No. 7,318,931 to Okumu et al. A bioerodible polymer decomposes when placed inside an organism, as measured by a decline in the molecular weight of the polymer over time. Polymer molecular weights can be determined by a variety of methods including size exclusion chromatography (SEC), and are generally expressed as weight averages or number averages.
  • SEC size exclusion chromatography
  • a polymer is bioerodible if, when in phosphate buffered saline (PBS) of pH 7.4 and a temperature of 37° C, its weight-average molecular weight is reduced by at least 25% over a period of 6 months as measured by SEC.
  • PBS phosphate buffered saline
  • Liposomes are well known as drug delivery vehicles. Liposome preparation is described in European Patent Application Publication No. EP 1332755 by Weng et al. Liposomes can incorporate short oligopeptide sequences capable of targeting the EGFR receptor, as described in United States Patent Application Publication 2012/0213844 by Huang et al. Alternatively, liposomes can include nuclear localization signal/fusogenic peptide conjugates and form targeted liposome complexes, as described in United States Patent Application Publication 2012/0183596 to Boulikas. [0481] The use of microspheres for drug delivery is known in the art and is 82described, for example, in H. Okada & H.
  • the drug conjugate form can be, but is not limited to, a drug conjugate form selected from the group consisting of: (a) polyethylene glycols; (b) polylactides; (c) polyglycolides; (d) amino acids; (e) peptides; and (f) multivalent linkers.
  • a drug conjugate form selected from the group consisting of: (a) polyethylene glycols; (b) polylactides; (c) polyglycolides; (d) amino acids; (e) peptides; and (f) multivalent linkers.
  • Polylactide conjugates are well known in the art and are described, for example, in R. Tong & C.
  • Thiol groups are known to have reactivity with a large number of coupling agents, such as alkyl halides, haloacetyl derivatives, maleimides, aziridines, acryloyl derivatives, arylating agents such as aryl halides, and others. These are described in G. T. Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996), pp. 146-150.
  • the reactivity of the cysteine residues can be optimized by appropriate selection of the neighboring amino acid residues. For example, a histidine residue adjacent to the cysteine residue will increase the reactivity of the cysteine residue.
  • Other combinations of reactive amino acids and electrophilic reagents are known in the art.
  • electrophilic reagents are known that will react with the ⁇ -amino group of the side chain of lysine, including, but not limited to, isothiocyanates, isocyanates, acyl azides, N- hydroxysuccinimide esters, sulfonyl chlorides, epoxides, oxiranes, carbonates, imidoesters, carbodiimides, and anhydrides. These are described in G.T. Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996), pp. 137-146.
  • electrophilic reagents are known that will react with carboxylate side chains such as those of aspartate and glutamate, such as diazoalkanes and diazoacetyl compounds, carbonydilmidazole, and carbodiimides. These are described in G. T. Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996), pp. 152-154. Furthermore, electrophilic reagents are known that will react with hydroxyl groups such as those in the side chains of serine and threonine, including reactive haloalkane derivatives. These are described in G. T. Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996), pp. 154-158.
  • amino groups can be reacted with isothiocyanates, isocyanates, acyl azides, N- hydroxysuccinimide (NHS) esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, alkylating agents, imidoesters, carbodiimides, and anhydrides.
  • Thiol groups can be reacted with haloacetyl or alkyl halide derivatives, maleimides, aziridines, acryloyl derivatives, acylating agents, or other thiol groups by way of oxidation and the formation of mixed disulfides.
  • the compound analog can be, but is not limited to, a compound analog selected from the group consisting of: (a) alteration of side chains to increase or decrease lipophilicity; (b) additional chemical functionalities to alter reactivity; (c) alteration of electron affinity; (d) alteration of binding capacity; and (e) salt forms.
  • the prodrug system can be, but is not limited to, a prodrug system selected from the group consisting of: PATENT EDISON-58717 (a) enzyme sensitive esters; (b) dimers; (c) Schiff bases; (d) pyridoxal complexes; (e) caffeine complexes; and (f) bioreductive analogs as prodrugs including nitroso-substituted analogs.
  • PATENT EDISON-58717 a prodrug system selected from the group consisting of: PATENT EDISON-58717 (a) enzyme sensitive esters; (b) dimers; (c) Schiff bases; (d) pyridoxal complexes; (e) caffeine complexes; and (f) bioreductive analogs as prodrugs including nitroso-substituted analogs.
  • the term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug is a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound as described herein.
  • the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug can be inactive when administered to a subject, but is then converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood or a tissue).
  • hydrolysis e.g., hydrolysis in blood or a tissue
  • a prodrug has improved physical and/or delivery properties over a parent compound from which the prodrug has been derived.
  • the prodrug often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (H.
  • prodrugs Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7-9, 21-24), incorporated herein by this reference.
  • a discussion of prodrugs is provided in T. Higuchi et al., “Pro-Drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and in E.B. Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987).
  • Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, enhanced absorption from the digestive tract, or enhanced drug stability for long-term storage.
  • prodrugs include, but are not limited to, formate or benzoate derivatives of an alcohol or acetamide, formamide or benzamide derivatives of a therapeutically active agent possessing an amine functional group available for reaction, and the like.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the carboxylic acid group with a group such as C1-8 alkyl, C2-12 alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)eth
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1 -((C 1 - C6))alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl (C1-C6)alkoxycarbonyloxymethyl, N(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, ⁇ -amino(C1-C4)alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, P(O)
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR′- PATENT EDISON-58717 carbonyl where R and R′ are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R- carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, C(OH)C(O)OY 1 wherein Y 1 is H, (C 1 -C 6 )alkyl or benzyl, C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C 1 - C6)alkyl, carboxy(C1-C6)alkyl,
  • the multiple drug system can be, but is not limited to, a multiple drug system selected from the group consisting of: (a) inhibitors of multi-drug resistance; (b) specific drug resistance inhibitors; (c) specific inhibitors of selective enzymes; (d) signal transduction inhibitors; (e) repair inhibition; and (f) topoisomerase inhibitors with non-overlapping side effects.
  • PATENT EDISON-58717 Multi-drug resistance inhibitors are described in United States Patent No. 6,011,069 to Inomata et al.
  • Specific drug resistance inhibitors are described in T.
  • the biotherapeutic enhancement can be, but is not limited to, use as a sensitizer or potentiator with a biological response modifier selected from the group consisting of: (a) cytokines; (b) lymphokines; (c) therapeutic antibodies such as bevacizumab, trastuzumab, rituximab, and cetuximab; (d) gene therapies; (e) ribozymes; (f) RNA interference, and (g) cell based therapeutics.
  • a biological response modifier selected from the group consisting of: (a) cytokines; (b) lymphokines; (c) therapeutic antibodies such as bevacizumab, trastuzumab, rituximab, and cetuximab; (d) gene therapies; (e) ribozymes; (f) RNA interference, and (g) cell based therapeutics.
  • the radiation therapy enhancement can be used in combination with a method or agent for radiation therapy that can be, but is not limited to, a method or agent for radiation therapy selected from the group consisting of: (a) hypoxic cell sensitizers; (b) radiation sensitizers/protectors; (c) photosensitizers; (d) radiation repair inhibitors; (e) thiol depletion; (f) vaso-targeted agents; (g) use with radioactive seeds; (h) use with radionuclides; (i) use with radiolabeled antibodies; and (j) use with brachytherapy.
  • Hypoxic cell sensitizers are described in C.C.
  • the improvement can be, but is not limited to, administration of a therapeutically effective quantity of elesclomol or a derivative or analog of elesclomol to reverse resistance to either platinum-containing anti- neoplastic agents or PARP inhibitor anti-neoplastic agents in malignant cells.
  • the platinum-containing anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin, satraplatin, and tetraplatin.
  • the PARP inhibitor is selected from the group consisting of iniparib, talazoparib, olaparib, rucaparib, veliparib, CEP- 9722 (a prodrug of CEP-8983 (11-methoxy-4,5,6,7-tetrahydro-1H- cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione), MK 4827 ((S)-2-(4-(piperidin-3- yl)phenyl)-2H-indazole-7-carboxamide), and BGB-290.
  • Other PARP inhibitors are described herein.
  • FIG. 21 shows that loss-of-function mutations in ARID1A both promote oncogenesis and increase reliance on OXPHOS for tumor cells.
  • the loss-of-function mutation significantly enhances DNA replication, diminishes the capacity for DNA repair, and causes increased mitotic activity and cell division, leading to malignant transformation.
  • Another aspect of the claimed invention is a method for treatment of a malignancy by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol as described above comprising the steps of: (a) administration of a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (b) administration of a therapeutically effective quantity of a microtubulin stabilizer or a microtubulin inhibitor.
  • the malignancy is OCCC.
  • the malignancy is OCCC that has progressed beyond FIGO stage 1.
  • the malignancy is OCCC occurring in a patient with a loss-of-function mutation in ARID1A.
  • the microtubulin stabilizer is typically paclitaxel or an analog of paclitaxel.
  • the microtubulin stabilizer can be docetaxel.
  • the microtubulin inhibitor is typically a vinca alkaloid selected from the group consisting of vincristine, vinblastine, vinorelbine, vinflunine, and vindesine.
  • Yet another aspect of the claimed invention is a method for treatment of a malignancy treatable by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol as described above comprising: PATENT EDISON-58717 (a) administration of a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (b) administration of a therapeutically effective quantity of a glutamine metabolism inhibitor.
  • the malignancy is OCCC.
  • the malignancy is OCCC that has progressed beyond FIGO stage 1 or has metastasized.
  • the malignancy is OCCC occurring in a patient with a loss-of-function mutation in ARID1A.
  • PATENT EDISON-58717 [0537]
  • the agent that inhibits the homologous repair pathway is imatinib mesylate or erlotinib.
  • Still another aspect of the claimed invention is a method for treatment of a malignancy treatable by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol as described above comprising: (a) administration of a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (b) administration of a therapeutically effective quantity of an agent that is activated by bioreductases under acute conditions of hypoxia or that functions to sensitize hypoxic cells to antineoplastic agents or radiation.
  • the malignancy is OCCC.
  • the malignancy is OCCC that has progressed beyond FIGO stage 1 or has metastasized.
  • the malignancy is OCCC occurring in a patient with a loss- of-function mutation in ARID1A.
  • the agent that is activated by bioreductases under acute conditions of hypoxia is selected from the group consisting of tirapazamine and mitomycin C.
  • Yet another aspect of the claimed invention is a method for treatment of a malignancy treatable by administration of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol as described above comprising: (a) administering a therapeutically effective quantity of elesclomol or a derivative, analog, salt, solvate, or prodrug of elesclomol; and (b) administering a therapeutically effective quantity of an agent that inhibits cysteine uptake.
  • the malignancy is OCCC.
  • the malignancy is OCCC that has progressed beyond FIGO stage 1 or has metastasized.
  • the malignancy is OCCC occurring in a patient with a loss-of-function mutation in ARID1A.
  • Agents that inhibit cysteine uptake include L-glutamate, L-aspartate, threo- ⁇ -hydroxyaspartate, dihydrokainate, threo- ⁇ -benzyloxyaspartate, peptides derived from digestion of human ⁇ -casein, bovine ⁇ -casein, and gliadin, erastin, analogs of erastin, sorafenib, and sulfasalazine.
  • the composition is formulated for treatment of a malignancy, and wherein the elesclomol or the derivative, analog, salt, solvate or prodrug of elesclomol is elesclomol itself
  • the composition is formulated for administration of a therapeutically effective quantity of elesclomol, wherein the therapeutically effective quantity of elesclomol is from about 1 mg/mm 2 /day to about 10 g/mm 2 /day. More typically, the therapeutically effective quantity of elesclomol is from about 2 mg/mm 2 /day to about 10 g/mm 2 /day. In another alternative, the therapeutically effective quantity of elesclomol is from about 1 ⁇ g/kg to about 500 mg/kg.
  • compositions and carriers include, but are not limited to: preservatives; sweetening agents for oral administration; thickening agents; buffers; liquid carriers; wetting, solubilizing, or emulsifying agents; acidifying agents; antioxidants; alkalinizing agents; carrying agents; chelating agents; colorants; complexing agents; suspending or viscosity-increasing agents; flavors or perfumes; oils; penetration enhancers; polymers; stiffening agents; proteins; carbohydrates; bulking agents; and lubricating agents.
  • agents for pharmaceutically active substances are well known in the art, and suitable agents for inclusion into dosage forms can be chosen according to factors such as the quantity of elesclomol or derivative, analog, salt, solvate, or prodrug of elesclomol, and, if present, other active agent or agents to be included per unit dose, the intended route of administration, the physical form of the dosage form, and optimization of patient compliance with administration. Except insofar as any conventional medium, carrier, or agent is PATENT EDISON-58717 incompatible with the active ingredient or ingredients, its use in a composition according to the present invention is contemplated.
  • compositions according to the present invention can be formulated for oral, sustained-release oral, buccal, sublingual, inhalation, insufflation, or parenteral administration.
  • Suitable routes for administration of pharmaceutical compositions according to the present invention can be chosen based on factors known to one of skill in the art including the unit dose of the elesclomol or the derivative, analog, salt, solvate, or prodrug of elesclomol, and, if present, the other active agent or agents, the particular carriers or excipients included in the composition, the intended route of administration, the disease or condition to be treated, its severity, other diseases or conditions affecting the patient and other factors known in the art.
  • a pharmaceutical composition according to the present invention is intended for oral administration, it is typically administered in a conventional unit dosage form such as a tablet, a capsule, a pill, a troche, a wafer, a powder, or a liquid such as a solution, a suspension, a tincture, or a syrup.
  • Oral formulations typically include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and other conventional pharmaceutical excipients.
  • oral pharmaceutical compositions will comprise an inert diluent and/or assimilable edible carrier, and/or they may be enclosed in hard or soft shell gelatin capsules. Alternatively, they may be compressed into tablets. As another alternative, particularly for veterinary practice, they can be incorporated directly into food. For oral therapeutic administration, they can be incorporated with excipients or used in the form of ingestible tablets, buccal tablets, dragees, pills, troches, capsules, wafers, or other conventional dosage forms.
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to materials of the above types, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form and properties of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar, or both.
  • the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes. [0554] In one alternative, a sustained-release formulation is used. Sustained-release formulations are well-known in the art.
  • sustained-release formulations incorporate a biodegradable polymer, such as the lactic acid-glycolic acid polymer disclosed in U.S. Patent No. 6,740,634 to Saikawa et al.
  • Still other sustained-release formulations incorporate an expandable lattice that includes a polymer based on polyvinyl alcohol and polyethylene glycol, as disclosed in U.S. Patent No.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, tinctures, or elixirs, or can be presented as a dry product for reconstitution with water or other suitable vehicles before use.
  • the preparations can also be emulsified.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions and/or dispersions; formulations including sesame oil, peanut oil, synthetic fatty acid esters such as ethyl oleate, triglycerides, and/or aqueous propylene glycol; and/or sterile powders for the extemporaneous preparation of sterile injectable solutions and/or dispersions.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the form In all cases the form must be sterile and/or must be fluid to the extent that the solution will pass readily through a syringe and needle of suitable diameter for administration. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria or fungi. [0557] For administration of the elesclomol or the derivative, analog, salt, solvate, or prodrug of elesclomol or of a pharmaceutical composition containing the elesclomol or the derivative, analog, salt, solvate, or prodrug of elesclomol, various factors must be taken into account in setting suitable dosages.
  • these factors include other medications being administered to the subject, which, in some cases, may alter the pharmacokinetics of the elesclomol or the derivative, analog, salt, solvate, or prodrug of elesclomol, either causing it to be degraded more rapidly or more slowly.
  • These medications can, for example, affect either liver or kidney function or may induce the synthesis of one or more cytochrome P450 enzymes that can metabolize the elesclomol or the derivative, analog, salt, solvate, or prodrug of elesclomol.
  • PATENT EDISON-58717 [0558] The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
  • Figure 16 is a series of graphs showing the effects of a 72-hour treatment with elesclomol on the viability of either the OVCA429 NTC (non-targeted control) clear cell ovarian cancer cell line or the OVCA429 ARID1A mutant cell line.
  • Figure 20 is a schematic diagram showing the mechanisms of action of elesclomol in cells with wild-type ARID1A and in mutant ARID1A, in particular the occurrence of reactive oxygen species (ROS) in cells with mutant ARID1A induced by elesclomol, leading to cytotoxicity in such cells.
  • ROS reactive oxygen species
  • the results of this example demonstrates the utility of the use of elesclomol, particularly in the treatment of clear cell ovarian cancer.
  • Example 2 Therapeutic Potential of Elesclomol in SWI/SNF-Mutant Cancer (Prophetic Example) [0567]
  • SWI/SNF complex is a key regulator of multiple cellular pathways frequently mutated in cancer.
  • the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes are evolutionarily conserved multi-subunit protein complexes that were first discovered in yeast as necessary for growth in the presence of different carbon sources (1-3).
  • SCCOHT cells are more sensitive to ROS inducing agents, including hydrogen peroxide and elesclomol, than SWI/SNF-intact ovarian cancer cells.
  • ROS reactive oxygen species
  • SMARCA4-deficient ovarian and lung cancer cell lines with or without SMARCA2 deficiency will include: (1) SMARCA4-deficient ovarian and lung cancer cell lines with or without SMARCA2 deficiency; (2) SMARCB1-deficient malignant rhabdoid tumor, epithelioid sarcoma and poorly differentiated chordoma cell lines; (3) ARID1A/B-dual deficient ovarian and uterine cancer cell lines.
  • SWI/SNF-intact ovarian, uterine, lung and brain cancer cell lines and non-transformed cell lines will be used as controls.
  • In vitro testing will be performed. In particular, short-term growth and long-term clonogeneic assays will be performed to evaluate the potency of elesclomol on SWI/SNF- deficient cancer cell lines.
  • Transcriptomic, proteomic and global metabolomic profiles of isogenic SCCOHT, DDC and lung cancer cells, -/+ SMARCA4 re-expression will be obtained by RNA sequencing and mass spectrometry to identify how elesclomol impacts the molecular profiles of SMARCA4/2- mutant cancer cells. Integrated analysis of these dataset will identify key molecular pathways that explains the SWI/SNF-dependent hypersensitivity to elesclomol. [0576] Additionally, direct targets of elesclomol will be identified by thermal proteome profiling (TPP). TPP entails subjecting intact cells or protein lysates, in the presence and absence of a small molecule, to temperature gradient to precipitate insoluble heat-denatured proteins.
  • TPP thermal proteome profiling
  • TPP exploits the thermodynamic changes to protein stability that occur upon binding to a small molecule and can be used to identify even rare proteins that are thermally affected by such interactions (42).
  • the advantage of hypersensitivity of SCCOHT cells to elesclomol and the low mutation burden of these cells and perform TPP analysis on two SCCOHT cells -/+SMARCA4 in the absence or presence of elesclomol will be exploited to determine the proteomic effect of elesclomol.
  • gRNA sequences will be determined by targeted sequencing with Illumina pair-end sequencing platform through BC Genome Science Centre.
  • Example 2 (a prophetic example) are as follows: 1 Neigeborn, L. & Carlson, M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics 108, 845-858 (1984).
  • SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proceedings of the National Academy of Sciences 109, E252-259, doi:10.1073/pnas.1114817109 (2012). Wong, A. K. et al. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res 60, 6171-6177. (2000). Jelinic, P. et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.
  • Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res.73, 5508-5518, doi:10.1158/0008- 5472.CAN-12-4593 (2013).
  • Wilson, B. G. et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol. Cell. Biol.34, 1136-1144, doi:10.1128/MCB.01372- 13 (2014). Hoffman, G. R. et al.
  • Histone Deacetylase Inhibitors Synergize with Catalytic Inhibitors of EZH2 to Exhibit Antitumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type. Mol. Cancer Ther.17, 2767-2779, doi:10.1158/1535-7163.MCT-18-0348 (2016). 34 Watanabe, M. et al. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. Int. J. Cancer 124, 55-67, doi:10.1002/ijc.23897 (2009). 35 Wang, Y. et al.
  • the histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol.242, 371-383, doi:10.1002/path.4912 (2017). 36 Chan-Penebre, E. et al. Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Mol. Cancer Ther.16, 850-860, doi:10.1158/1535-7163.MCT-16-0678 (2017). 37 Lang, J. D. et al.
  • Example 3 Investigation of the Therapeutic Potential of Elesclomol in Clear Cell Ovarian Cancer [0579] The impact of elesclomol on proliferation, migration/invasion, and tumorigenic potential of clear cell ovarian cancer (CCOC) cell lines will be investigated. The initial focus will be on CCOC cell lines harboring an ARID1A mutation; specifically, OVISE, OVMAMA, PATENT EDISON-58717 and JHOC-7 cell lines. The IC 50 for elesclomol in these cells will be determined.
  • a determination of whether elesclomol impacts the aggressive phenotype of CCOC cells will be made; it is postulated that elesclomol impairs cell adaptation to stress and thus inhibits a migratory/invasiveness phenotype.
  • the effects of elesclomol on cell viability will be determined using crystal violet, cell proliferation using Ki67, cell death using caspase-3 activation assay and western blotting, generation of reactive oxygen species (ROS) using H2DCFDA, CellROX and FACS analysis, independent cell growth using soft agar colony formation assay, migration using scratch assay and in vitro migration assay, as well as invasiveness capacity using an in vitro invasion assay.
  • ROS reactive oxygen species
  • Ovarian clear-cell carcinoma is a chemoresistant subtype of ovarian cancer, accounting for approximately 10% of all epithelial ovarian carcinoma in north America and up to 30% of epithelial ovarian carcinoma cases in Japan.
  • ARID1A a subunit of the SWI/SNF complex, is mutated in roughly 65% of CCOC cases, playing a pivotal role in CCOC development.
  • FIG. 23 A schematic of the ARID1A mutation and elesclomol (EO3001)-induced cell death by cuproptosis is shown in Figure 23.
  • the pulmonary metastasis assay (PuMA) originally designed for sarcomas, offers a more biologically relevant environment than traditional two-dimensional and three- dimensional models for studying the underlying biology and therapy response of OCCC. (M.M. Lizardo & P.H. Sorensen, “Practical Considerations in Studying Metastatic Lung Colonization in Osteosarcoma Using the Pulmonary Metastasis Assay,” J. Vis. Exp. (133): 56332 (2016)).
  • FIG. 24 A comparison of models currently used in cancer research is shown in Figure 24; the models depicted and compared include two-dimensional culture; three-dimensional culture (organoid); animal; and PuMA.
  • PuMA fluorescent-tagged RMG1 and JHOC5 cell lines with either wild-type ARID1A or mutant ARID1A were generated using CRISPR/Cas9.
  • the OCCC cell lines with the fluorescent tags were then injected into mice by tail vein infection and allowed to settle for hours to days.
  • the cells are allowed to grow and form lung metastases, typically over a period of 2.5 months.
  • the lung was then inflated with special agarose gel dissolved in media, solidified, and sectioned into 3-4 mm pieces.
  • the lung sections were grown on sponge soaked with PneumaCultTM media and treated with either vehicle or elesclomol for up to 21 days; fluorescent metastatic cells were able to interact with this framework and subsequently develop into metastatic colonies, and the growth PATENT EDISON-58717 of cancer cells was visualized using epifluorescence or confocal microscopy.
  • the process is shown in Figure 25. [0587]
  • the results show that ARID1A-mutant cell lines are selectively sensitive to elesclomol in vitro under ambient (normoxic) conditions, with lesser effects shown under hypoxic conditions.
  • panel (A) shows the ARID1A profile of OCCC cell lines (OVISE, OVMANA, RMG1, CAOV3, JHOC5, JHOC7, and JHOC9) shown by western blotting
  • panel (B) shows the IC 50 for elesclomol on OCCC cell lines (OVISE, OVMANA, RMG1, JHOC5, and JHOC9) in a 72-hour MTT assay
  • panel (C) shows the ARID1A profile of RMG1 and JHOC5 cells (with wild-type ARID1A shown to the left and mutant ARID1A shown to the right for each cell line) by western blotting
  • panel (D) is a graph showing that the IC50 decreases for RMG1 and JHOC5 cells for mutant ARID1A (shown to the right for each cell line) as compared with cells with wild-type ARID1A (shown to the left for each cell line);
  • panel (E) is a graph showing that hypoxia decreases the relative effect
  • Figure 27 shows that RMG1 cells with mutant ARID1A grown in PuMA show higher sensitivity to elesclomol.
  • Panel (A) of Figure 27 shows the growth of RMG1 cells with wild-type ARID1A (NTC) and mutant ARID1A without elesclomol (Ct, left portion) and with 60 nM elesclomol (right portion) in the PuMA model over time shown by serial images;
  • panel (B) shows the quantification of growth by the mean of the fluorescence intensity;
  • panel (C) shows the gross pathology (top portion), hematoxylin-eosin (H&E) staining (central portion) and HNF1 ⁇ -IHC stained sections (lower portion) from the PuMA assay (wild-type ARID1A, left side; mutant ARID1A, right side).
  • ADVANTAGES OF THE INVENTION [0590] The present invention provides improved methods and compositions for treatment of malignancies and other diseases and conditions, including, but not limited to, benign hyperproliferative diseases and conditions, infections, inflammatory diseases and conditions, and immunological diseases and conditions. Elesclomol functions by elevating oxidative stress levels, particularly in cancer cells.
  • Methods and compositions according to the present invention are well-tolerated and can be used together with other methods and therapeutic agents for treating malignancy, as well as other diseases.
  • Methods and compositions according to the present invention are particularly directed to the treatment of ovarian clear-cell carcinoma (OCCC), especially OCCC that has progressed beyond FIGO stage 1 or OCCC that has metastasized, including, but not limited to, metastasis in an organ selected from the group consisting of the lung, the stomach, and the brain.
  • OCCC ovarian clear-cell carcinoma
  • transitional phrase “comprising” and equivalent language also encompasses the transitional phrases “consisting essentially of” and “consisting of” with respect to the scope of any claims presented herein, unless the narrower transitional phrases are explicitly excluded.
  • Methods according to the present invention possess industrial applicability for the preparation of a medicament for the treatment of diseases or conditions described herein, including, but not limited to, malignancy. Methods according to the present invention also possess industrial applicability for use in treating such diseases and conditions, including, but not limited to, malignancy. Compositions according to the present invention possess industrial applicability as pharmaceutical compositions, particularly for the treatment of malignancy, as well as for other diseases and conditions described above.

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Abstract

La présente invention concerne des méthodes et des compositions utilisant de l'élesclomol ou des dérivés ou des analogues de celui-ci pour le traitement de malignités, en particulier le carcinome ovarien à cellules claires (OCCC), plus particulièrement, l'OCCC qui a progressé au-delà du stade 1 de la classification FIGO ou qui a métastasé.
PCT/US2024/049622 2023-10-04 2024-10-02 Utilisation d'élesclomol pour le traitement des cancers ovariens à cellules claires avec des mutations de l'arid1a Pending WO2025076109A1 (fr)

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CN121059779A (zh) * 2025-09-10 2025-12-05 上海敦庞实业发展有限公司 一种血耳石斛植物制剂的制备方法及其在妇科内分泌疾病中的应用

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US20130150440A1 (en) * 2010-04-20 2013-06-13 Synta Pharmaceuticals Corp. Use of bis [thiohydrazide amide] compounds such as elesclomol for treating cancers
WO2023069727A1 (fr) * 2021-10-21 2023-04-27 Edison Oncology Compositions et méthodes pour le traitement de maladies hyperprolifératives, inflammatoires et immunologiques, et d'infections

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US20130150440A1 (en) * 2010-04-20 2013-06-13 Synta Pharmaceuticals Corp. Use of bis [thiohydrazide amide] compounds such as elesclomol for treating cancers
WO2023069727A1 (fr) * 2021-10-21 2023-04-27 Edison Oncology Compositions et méthodes pour le traitement de maladies hyperprolifératives, inflammatoires et immunologiques, et d'infections

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN121059779A (zh) * 2025-09-10 2025-12-05 上海敦庞实业发展有限公司 一种血耳石斛植物制剂的制备方法及其在妇科内分泌疾病中的应用

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